Frequency modulated drug delivery (FMDD)

ABSTRACT

Embodiments of the present disclosure include a coordination complex, comprising a first biologically active moiety, a second biologically active moiety, and a metal, wherein the first biologically active moiety and second biologically active moiety are bound to the metal by covalent coordination bonds, and wherein the first biologically active moiety and second biologically active moiety are different. These complexes may enhance the pharmacodynamic properties of biologically active moieties.

REFERENCE TO EARLIER FILED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/316,259, filed Dec. 9, 2008, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Combination drug therapy has become a critical tool in the treatment ofmany disease states. Using two or more therapeutic agents withcomplementary mechanistic actions has been shown to hasten theresolution and reduce the severity of certain disease states moreeffectively than is possible with either agent alone. While exploitingthe potential synergies between the agents and minimizing their sideeffects has always been the goal of combination drug therapy,combination strategies have also been shown to lower treatment failure,case-morbidity and mortality rates, slow the development of resistant orrefractory cases, lower overall healthcare costs, and improve patients'overall quality of life. As our knowledge of the mechanisms of diseaseexpands, advanced combination therapeutic strategies can improve theoutcome of pharmaceutical intervention in these disease states.

SUMMARY OF THE INVENTION

Embodiments of the present disclosure include a coordination complex,also known as a coordination compound, comprising a first biologicallyactive moiety, a second biologically active moiety, and a metal, whereinthe first biologically active moiety and second biologically activemoiety are each bound to the metal by at least one binding site, whereinthe first biologically active moiety and second biologically activemoiety are different, and wherein the first biologically active moietyand the second biologically active moiety both have a biological effecton a target tissue.

Other embodiments include a method for enhancing pharmacodynamicproperties of biologically active moieties, by forming a coordinationcomplex comprising a first biologically active moiety, a secondbiologically active moiety, and a metal, wherein the first biologicallyactive moiety and the second biologically active moiety are each boundto the metal by at least one binding site, and wherein the firstbiologically active moiety and the second biologically active moiety aredifferent.

Further embodiments of the present disclosure include a method oftreatment, including administering a coordination complex comprising atleast a first biologically active moiety, a second biologically activemoiety, and a metal, wherein the first biologically active moiety andthe second biologically active moiety both have a biological effect on atarget tissue.

BRIEF DESCRIPTION OF THE FIGURES

For a better understanding of the embodiments of the present disclosure,reference is made to the figures contained herein:

FIG. 1 illustrates that pain transmission can occur throughvoltage-dependant calcium channels releasing neurotransmitters (Glu,Substance P and BDNF), which activates the NMDA receptor and propagatingthe pain signal;

FIG. 2 illustrates a low dose opioid binding to its receptor generatinga signal to release less neurotransmitter, which in turn, reduces theintensity of the propagation signal;

FIG. 3 shows the DOP antagonist, 7′-aminonaltrindole, and the MOPagonist, oxymorphamine, linked with a hexyldiamine glycolate spacer;

FIG. 4 shows that with FMDD, the low dose opioid of the magnesiumcomplex slows release of the neurotransmitters similar to that shown inFIG. 2, but the residual glutamate is blocked by the NMDA-R antagonistreleased from the magnesium complex (the ligand-magnesium bond breakingis designated by the dashed lines). Thus both the opioid and the NMDA-Rantagonist potentiate the effects of each other in a manner thatkinetically approximates the mechanism of pain signal propagation;

FIG. 5 shows the chemical structure for ARL 15896AR;

FIG. 6 shows the chemical structure for remacemide;

FIG. 7 shows the chemical structure for ACEA1328;

FIG. 8 shows the chemical structure for ACPC;

FIG. 9 shows the chemical structure for ZD9379;

FIG. 10 shows the chemical structure of oxycodone;

FIG. 11 shows the chemical structure of morphine;

FIG. 12 shows the chemical structure of remacemide:Mg:M6 GHA;

FIGS. 13 a and 13 b show simplified schematic diagram of the basalganglia circuit in both the normal and Parkinsonian states. InhibitoryGABAergic projections are indicated by shaded arrows, excitatoryglutamatergic projections are indicated by open arrows. A box and blackarrow indicates the modulatory dopaminergic nigrostriatal pathway. Notethat the loss of dopaminergic modulation of the striatum results in anincrease in glutamatergic output from the subthalamic nucleaus to boththe basal ganglia output nuclei and the substantia nigra dopamineneurons. GPe=globus pallidus external segment; GPi=globus pallidusinternal segment; SNc=substantia nigra pars compacta; SNr=substantianigra pars reticulata; STN=subthalamic nucleus; Thal=thalamus.

FIG. 14 shows the chemical structure for (DOPA)calcium(carnosine);

FIG. 15 shows the chemical structure for (DOPA)magnesium(carnosine);

FIG. 16 shows the chemical structure of (SAHA)magnesium(mercaptopurine);

FIG. 17 shows the chemical structure of (SAHA)magnesium(remacemide);

DETAILED DESCRIPTION OF THE INVENTION

In many combination pharmaceutical applications, simultaneouslydelivering two or more pharmaceutical agents in a kinetically orfrequency modulated synergistic manner may further potentiate thebeneficial effects of the respective agents. This synergistic deliverymay be facilitated if the respective agents were introduced into thebody as a single integral molecular entity.

Simply delivering a combination drug as a single molecular entity,however, does not ensure efficacy. For example, when pullalan andinterferon were covalently bound into a single molecule, the pullalanportion of the conjugated drug interfered with the binding of interferonto the liver cell surface receptor, thereby preventing induction of theantiviral enzyme, 2-5AS and rendering the conjugated drug ineffectiveagainst hepatitis. (Y. Suginoshita et al., Liver Targeting ofInterferon—with a Liver-Affinity Polysaccharide Based on MetalCoordination in Mice, J. Pharmacol. Exp. Ther., 2001, 298 (2), 805-811).

Only when the two were combined as a metal complex did interferon bindeffectively to cell surface receptor, while still retaining the livertargeting properties provided by the pullalan moiety. This notion ofcombining agents as metal complexes is further supported by thecomplexation of polyarginine and a peptide analog with nickel to createa peptide with enhanced cellular transfection efficiency. (S. Futaki etal., Arginine Carrier Peptide Bearing Ni(II) Chelator to PromoteCellular Uptake of Histidine-Tagged Proteins, Bioconjug Chem, 2004, 15(3), 475-81). These examples show that a bond between a metal andpharmaceutical ligand can both impart the thermodynamic stabilitynecessary to deliver the drug to its target and be labile enough toallow the drug to retain its biological activity.

Approaches to facilitate the delivery of the combination products havefocused on the process known as co-crystallization. By and large, theadvantages that co-crystals provide to the pharmaceutical compoundsinclude improved solubility, bioavailability, stability andhygroscopicity. The vast majority of the co-crystallization processesrely on hydrogen bonding, Van der Waal forces, ionic bonding andlipophilic interactions between the components of the co-crystal. Inonly one example is metal coordination chemistry, namely(ibuprofen)₄Cu₂(caffeine)₂, utilized to facilitate the formation ofco-crystals of pharmaceutical agents. (Zhenbo Ma & Brian Moulton,Supramolecular Medicinal Chemistry: Mixed-Ligand Coordination Complexes,Molecular Pharmaceutics, 2007, 4(3), 373-385).

The concept of combining pharmacophore fragments into a single molecularentity is a novel approach to combination pharmaceutical products. Thisapproach relies on in silico techniques to design the molecular scaffoldthat retains the therapeutic portions of the pharmaceutical components,while eliminating the toxic parts. To the best of our knowledge, noexamples of using metals to combine the different pharmacophorefragments have been reported.

The present disclosure contemplates administration of pharmaceutical orbiologically active agents in a manner known as “frequency modulateddrug delivery,” or “FMDD.” FMDD is a method whereby a combination ofbiologically active agents, which can potentiate or have a positiveimpact on the respective pharmacodynamics or biological effects, aredelivered in such a manner that the respective kinetics aresynergistically optimized. This kinetic synergy is best accomplishedwhen the two biologically active agents are part of the same molecule.In that way, delivery to various tissue loci or the same tissue loci isgreatly facilitated. FMDD is further defined by the method ofsynergistically delivering the biologically active agents such that thetwo biologically active agents are part of the same molecule yet stillhave the capacity to interact with their respective receptors withminimum interference from the other biologically active agent. Thus, asan embodiment of this invention, the FMDD composition is twobiologically active agents that are combined as a single molecularentity through metal coordination complexation such that the twobiologically active agents are delivered to a target tissue in akinetically synergistic manner. This kinetic synergy may be increasedover two biologically active moieties that are introduced together butare not part of the same complex.

In embodiments of the coordination complexes described herein, the firstbiologically active moiety and the second biologically active moietyboth have a biological effect on a target tissue, which may or may notbe the same tissue. In certain embodiments, however, both the firstbiologically active moiety and the second biologically active moiety dohave a biological effect on a same target tissue. In some embodiments,the first biologically active moiety and the second biologically activemoiety have a biological effect on a tissue associated with the samedisease state, though the two moieties may not have a biological effecton the same tissue. In other embodiments, though, the first biologicallyactive moiety and the second biologically active moiety do have abiological effect on a same target tissue associated with a diseasestate.

In certain embodiments of the coordination complexes described herein,the first biologically active moiety and the second biologically activemoiety have a biological effect on receptors on a tissue associated withthe same disease state, though the first and second moieties may nothave an effect on the same tissue, and may or may not have an effect onthe same receptors. In other embodiments, both the first biologicallyactive moiety and the second biologically active moiety have abiological effect on the same receptors on the same tissue associatedwith a same disease state. In still other embodiments, both the firstbiologically active moiety and the second biologically active moietyhave a biological effect on different receptors on the same tissueassociated with a same disease state.

In other embodiments of the coordination complexes described herein, themetal itself also has a biological effect on a target tissue. In someembodiments, the metal potentiates the biological effect of at least oneof the first biological moiety and the second biological moiety.

Certain embodiments of the present disclosure include a coordinationcomplex, comprising a first biologically active moiety, a secondbiologically active moiety, and a metal, wherein the first biologicallyactive moiety and second biologically active moiety are each bound tothe metal by at least one binding site, and wherein the firstbiologically active moiety and second biologically active moiety aredifferent. The first biologically active moiety may potentiate thebiological effect of the second biologically active moiety. Thispotentiating effect may be due to the increased kinetic synergy as aresult of their inclusion in a coordination complex.

Coordination Complex

This invention concerns coordination complexes having the formula:L₂-M-L₁wherein M is a suitable metal and each of L1 (ligand 1) and L2 (ligand2) is a pharmaceutical or biologically active agent or its anion formedby reaction of the agent with a base. In the complex, L1 and L2 arebound to M by covalent coordination bonds and L1 and L2 are differentfrom each other. As such, the compounds ML1 L2 constitute mixed ligandcomplexes (also called hetero-ligated complexes or compounds). Suitablemetals include, but are not limited to, Mg, Ca, Sr, Fe, Co, Ni, Cu, Zn,Pd, Pt, Ru, Rh, Al, and Sn.

The term “complex” in chemistry, also called a “coordination compound”or “metal complex”, includes a structure consisting of a central atom ormolecule, a metal, connected to surrounding atoms or molecules. The ionsor molecules surrounding the metal are called ligands. Ligands aregenerally bound to a metal ion through binding sites of the ligand by acoordinate covalent bond (donating electrons from a lone electron pairinto an empty metal orbital), and are thus said to be coordinated to theion. Coordination complexes typically have stability constants that fallbetween those of salts and classic covalent bonds. The stability ofcoordination complexes relies on the nature of the metal and the ligandsattached to the metal. Ligands with one binding site are calledmonodentate ligands. Ligands that can bond to a metal atom through twoor more binding sites or donor atoms participate in ring closure at themetal center. These ligands are known as ambidentate ligands, and thecompounds formed are known as chelation compounds. Chelation involvescoordination of more than one sigma-electron pair donor group from thesame ligand to the same metal atom. As such, chelation compounds are asubset of coordination compounds. Chelation is a critical component inthe stabilization of a coordination compound. Within the s-blockelements, this is particularly true for magnesium and calcium. Forexample, the log K_(eq) of the acetic acid-magnesium complex is 0.47.With the incorporation of an additional chelating atom, nitrogen, thecomplex becomes glycine-magnesium and the log K_(eq) increase to 1.34.Additional ligands, other than the initial ligand, can stabilize themetal-drug complex further. Adding salicylaldehyde to theglycine-magnesium complex, given by the reaction equilibriumMg²⁺+SA⁻+G⁻

Mg(SA)(G)further increases the log K_(eq) to 4.77. Clearly salicylaldehyde adds astabilizing effect to the magnesium glycine bond. This stabilizingeffect is also imparted by other chelating ligands such as dipyridyl orethylene diamine and N-alkyl analogs thereof.

Simple combinations of metals with ligands in solution do not alwaysproduce the same product. It is recognized that the salt of an organicacid is easily prepared by treating the acid with a base and a metalsalt where the expected product is the metal salt of the organic acid; amethod known by anyone skilled in the art. However, when coordinationchemistry contributes to the bonding between the organic acid and themetal, a variety of conditions, such as solvent, temperature and,perhaps most importantly, ligands attached to the metal, impact thestructure and the stability of the coordination complex.

The present disclosure is directed to coordination complexes fortreatment of disease and medical conditions in animals, with humansbeing a preferred embodiment. In these embodiments, the ligands includebiologically or pharmaceutically active agents or moieties. As usedherein, a biologically or pharmaceutically active agent or moiety is anagent used to treat a disease or medical condition. Agents withpotential for use in embodiments of the present disclosure may bereferred to as frequency modulated drug delivery, or “FMDD,” ligands.These FMDD ligands include the biologically or pharmaceutically activeagent, and also any other linker molecules or other components needed toform the complex. The FMDD ligands include at least one binding site ordonor atom. An FMDD ligand with one donor site is a monodentate FMDDligand, and an FMDD ligand with more than one binding site or donor atomis an ambidentate FMDD ligand. A complex formed with FMDD ligands may bereferred to as an FMDD complex. The FMDD complex may include the FMDDligands, the metal, and any other ingredient or component that may notnecessarily be bonded to the metal, yet is still part of the complex.

In the complexes L2-M-L1, L1 or L2 may have one donor group, calledmonodentate ligands. In other complexes, L1 or L2 may have more than onedonor group and are thus capable of occupying more than one coordinationsite. These ambidentate ligands can function as a bridge between metalcenters to form polynuclear or polymeric complexes, or participate inring closure at a single metal center to form chelate complexes. Thisinvention concerns coordination complexes of both types.

Coordination complexes with chelating ligands are thermodynamically morestable than those with similar ligands that do not chelate. Five- orsix-membered chelate rings are the most favored in coordinationcompounds. But compounds forming four- seven- and eight- and largermembered rings may also be stable. Embodiments of this inventionincludes coordination complexes containing four- five- six- seven- andeight-membered rings.

The nature of the bond between the ligand and the metal in acoordination complex is covalent in nature. This is critical to themechanism of the chemistry concertedly operating with the pharmacologydescribed in this invention. A pure ionic bond, such as that whichexists in a salt, will not retain the integrity of the moleculethroughout the time course required for synergistic effects of the twoor more respective ligands to be manifest. A bond between the ligandsthat is purely covalent would certainly survive the trials and travailsinherent in the organism on its way to the target organ but would not beable to elicit the pharmacologic effects of both reagents if they werecovalently tethered to each other. It is an embodiment of this inventionthat only a metal coordination complex possesses enough covalent bondstrength to retain the integrity of the hetero-ligated complex in thebody to the target site yet be labile enough to allow both biologicallyactive agents to impart their pharmacologic effect at the target site.

In preparative coordination chemistry mixed-ligand complexes are oftenprepared by reaction of a metal with a mixture of L1 and L2 or theirsalts (eq 1); reaction of a metal with L1 or its salt, followed byaddition and reaction of L2 or its salt (eq 2); or co-proportionation ofhomoleptic complexes (eq 3). This is shown below for the case of adivalent metal alkoxide reacting with HL1 and HL2:M(OBu)₂+HL₁+HL₂→ML₁L₂+2BuOH  (eq 1)M(OBu)₂+HL₁→M(L₁)(OBu)+BuOHM(L₁)(OBu)+HL₂→ML₁L₂+BuOH  (eq 2)M(L₁)₂+M(L₂)₂→2ML₁L₂  (eq 3)where Bu=butyl.

Mixed ligand complexes occur when a complex has two or more differentligands in its coordination sphere. There are a number of generalsynthetic approaches to prepare these compounds, which include: 1)Simultaneous combination of the two ligands; 2) Sequential combinationof the ligands; and 3) A reproportionation reaction between two binarybis-ligand complexes.M+L+L′

MLL′  (1)ML+L′

MLL′  (2)ML₂+ML′₂

2MLL′  (3)

In a solution containing a metal ion and ligands L and L′, the formationof the mixed ligand complex MLL′ is more favored on a statistical basis,than the formation of the binary complexes ML2 and ML′2. The equilibriumconstant for the formation of this mixed ligand complex is related tothe equilibrium constant of the corresponding reproportionationreaction, K_(reprop). If only statistical factors were responsible forformation of the mixed ligand complex, then K_(reprop)=4. As theexperimental values of K_(reprop) differ from the statistical value,other factors are involved in the formation of mixed ligand complexes.These factors can affect product formation by stabilizing ordestabilizing the complexes, and include electronic, electrostatic, andsteric effects. (P. K. Bhattacharya, Metal Ions in Biochemistry, AlphaScience International Ltd., 2005).

For example, the formation of an asymmetric metal coordination complexis favored thermodynamically, which is in part due to the increaseddegeneracy of the d-orbitals. (J. Watters & R. DeWitt, The Complexes ofNickel(II) Ion in Aqueous Solutions Containing Oxalate Ion andEthylenediamine, J. of Am. Chem. Soc., 1959, 82, 7). The favoredformation of monomomeric heteroligated metal coordination species wasobserved when a new ligand is added to homoligated dimeric metalcoordination complex. The occupation of the available coordination sitesin the homoligated species to produce a more asymmetric product was theapparent driving force for the formation of the heteroligated product.(E. J. Baran, Metal Complexes of Carnosine, Biochemistry, 1999, 65 (7),11).

Substitution reactions, in which the ligand in a metal complex isreplaced by a second ligand, are also used to prepare mixed ligandcomplexes.ML₂+L′

MLL′+L

These reactions depend not only on the thermodynamic stability of theligand binding with the metal ion, but on the mechanism of the reaction.Preparation of mixed-ligand complexes involves precise control of thefollowing reaction parameters: stoichiometry, solvent, temperature,concentration, order of addition of reagents, and isolation andpurification of the mixed-ligand complex.

The selection of the metal is determined by the application (i.e. thedisease state to be treated) and the nature of the drug ligands used inthe application. For drug ligands containing functional groups rich inoxygen (carboxylic acids, amides, esters, alcohols, ethers, etc) metalsof Group IIA, Group IIIB, and Group IVB are likely metals of choice.Magnesium and calcium are preferred metals of this invention due totheir generally regarded safety. For drug ligands containing nitrogen(amines, amides, etc) transition metals are likely metals of choice.

Coordination can be confirmed and differentiated from mixtures ofcomponents or formation of simple salts, by a variety of methodsincluding:

-   -   1. ¹H and ¹³C nuclear magnetic resonance spectroscopy, through        comparison of chemical shifts and changes of relaxation        parameters caused by coordinate covalent bond formation;    -   2. Infrared spectroscopy, through comparison of the stretching        of bonds or shifting of absorption caused by coordinate covalent        bond formation;    -   3. Mass spectrometry;    -   4. Molar conductivity or magnetic measurements; and    -   5. X-ray crystallography.

The key premise to this invention is that two or more biologicallyactive agents are bound together in such a fashion to approximate thekind of covalency inherent in carbon-heteroatom bonds. It is anembodiment of this invention that this kind of covalency can best beachieved using metal coordination chemistry. It is a further embodimentof this invention that the bond between the metal and the respectivebiologically active agent is labile enough that it would break once theentire hetero-ligated metal coordination complex comes in contact withanother biologically relevant entity such as a receptor for thebiologically active agent.

Once this first bond between the biologically active agent and the metalis broken, the second biologically active agent that is also bound tothe same metal is now available to bind to its receptor at a locationthat is kinetically synergistic to the first biologically active agent'sbinding to its receptor.

It is a critical component of this invention that the two biologicallyactive agents act on their respective receptors in such a manner thatthe biological effect of the two events are synergistically linked tomaximize the response at the receptor, thus minimizing the requirementby the receptor for the biologically active agent.

In a most preferred embodiment of the invention this synergy is impartedby coordinating both biologically active agents to a metal, such that anew composition of matter consisting of the two biologically activeagents and the metal is formed.

Synthesis of compound libraries as part of a drug discovery process incombinatorial chemistry has “taken its place as a synthetic tool,complementary to rational design, with the power to identify compoundswith beneficial biological, catalytic, binding, sensing, and materialproperties”. (M. Krier et al., Design of Small-sized Libraries byCombinatorial Assembly of Linkers and Functional Groups to a GivenScaffold Application to the Structure-based Optimization ofPhosphodiesterase 4 Inhibitor, J Med Chem 2005, 48 (11), 3816-22). Thismethod can quickly lead to large numbers of molecules. For example, amolecule with three points of diversity (R₁, R₂, and R₃) can generateN_(R1)×N_(R2)×N_(R3) possible structures, where N_(R1), N_(R2), andN_(R3) are the number of different substituents utilized. Infinitevariations on a core template are theoretically possible, making theselibraries difficult to screen and often difficult to synthesize. Inorder to gain the maximum amount of information from the minimum numberof experiments the current practice of rational combinatorial chemistryrequires the optimization of screening libraries, i.e. a minimal sizewith maximal chemical diversity. To limit the magnitude of library sizeto 10**2, computational chemists have developed algorithms to select arepresentative subset. “Virtual libraries are assessed by techniquesincluding Monte Carlo calculations, genetic algorithms, artificialneutral network, or simply statistical sampling with user-definedproperty ranges.”

Traditional combinatorial methods involve assembly of user-selectedbuilding blocks composed of a scaffold, attached to a linker, modifiedby a functional group. From a medicinal chemistry point of view, theselibraries are usually generated on the basis of known pharmacophores asscaffolds. We have developed a rational combinatorial chemistry programfor the discovery of metal coordinated pharmaceuticals.

Our approach is an adaptation where we utilize known pharmaceuticals asscaffolds, and metal ions as linkers. The functional group is selectedfrom a class of FMDD ligands capable of bonding to the metal, such as,but not limited to, amino acids, lipids, carbohydrates, nucleic acids,peptides, and bioadhesives, and chosen to improve PK properties. Thisapproach offers a number of advantages, including:

-   1) Development of a practical synthetic methodology based on    coordination chemistry which can be applied to a combinatorial    program;-   2) In contrast to most combinatorial programs, our linker is not a    passive participant, but is responsible in large part for the    improved pharmacokinetic properties of these molecules;-   3) Each molecule can be considered as a tool to probe the different    pharmacokinetic properties of the modified drug deriving from the    metal/FMDD ligand combination;-   4) Utilizing a subset of about 10 metals, and 20 FMDD ligands (for    the case of amino acids), the criteria of small-sized libraries    associated with each known trade drug is met. We believe certain    motifs of pharmacokinetically beneficial metal/FMDD ligand    combinations will arise allowing for further reduction in library    size when applied to compounds generated from different drug    scaffolds.

The mechanism by which kinetic synergy potentiates the pharmacologiceffect of biologically active agents can be explained in a variety ofways and depends on the disease state in question. The followingsections explain this concept as it applies to CNS disorders, cancer,cardiovascular diseases, inflammatory bowel diseases, pain and otherdisease states.

Use in Pain Management

The sensation of pain results from intense or high frequencystimulation, or potentially tissue damaging stimuli acting on cutaneousreceptors called nociceptors. Nociceptors respond to pressure, heat,cold and chemicals and their activation is modulated by the strength ofthe stimulus.

Sensation of stimuli, pain or touch, is transmitted from the peripheralsensory neurons to the afferent neurons, grouped into the excitatory,the sensitizing and the inhibitory. Stimuli resulting from tissue damageproduce an inflammatory array that acts on these groups of receptors invarying degrees, depending on the stimulus. Onward transmission of thesesignals to the CNS depends on the balance of inputs to and from thedorsal horn neurone in the spinal cord, all of which are regulated by acomplex array of neurotransmitter receptors and voltage-gated ionchannels (potassium, sodium and calcium).

Hyperalgesia, repeated noxious stimulus, and allodynia, non-noxiousstimulus that is perceived as pain, are initiated as peripheralsensitization of nociceptors leading to central sensitization wherespinal processing of the afferent inputs propagates the original painsignal. These central sensitization pre-synaptic neurons propagate andamplify the pain nociception by releasing neurotransmitters; the twomore important of these include substance P acting on the neurokinin-1(NK-1) receptor and glutamate acting on the N-methyl-D-aspartatereceptor (NMDA-R). Efforts to develop analgesics acting on the NK-1receptor have been unsuccessful, thus analgesic agents that act on theNMDA receptor have become important for the relief of hyperalgesia dueto chronic or neuropathic pain.

First order neurons terminate in the dorsal horn of the spinal cordwhere the electrochemical impulse opens voltage-gated calcium channelsin the presynaptic bouton. The resultant influx of calcium releasesglutamate into the synaptic space, which acts via theAlpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPA-R) to produce a rapid excitatory post-synaptic potential. Repeatedstimulation of AMPA receptors releases peptides, which causesdepolarization of the receptor membrane relieving the Mg block from thepore of the NMDA receptor. Released glutamate can now bind to andactivate the NMDA-R on the second order neuron leading to ahyper-excitable state (i.e. transmission of pain signal). This signalwill continue until the stimulus stops or the NMDA receptor is blocked.

Transmission of pain can be suppressed in the dorsal horn at thepre-synaptic level or post-synaptically on the dorsal horn neurone.Preventing depolarization of key receptors in the dorsal horn (e.g.glutamate receptors) can prevent pain and brain tissue damage. The NMDAreceptor is a powerful switch for central sensitization and turning thatreceptor off will block the hyperexcitability cascade and impart ananalgesic effect. Regulation of expression of NMDA and AMPA receptorsmay also have an impact on the excitatory condition. The NMDA receptoris divided into subunits that are binding sites for glutamate, glycine,magnesium, zinc and phenylglycidine.

Another important method of blocking pain involves the use of opioidreceptor agonists. The opioid system comprises the μ-opioid receptor(MOP), δ-opioid receptor (DOP) and the κ-opioid receptor (KOP), each ofwhich have an associated cognate ligand, opiomelanocortin, enkephalinand dynorphin, respectively. Opioid receptors are expressed on theterminals of 1⁰ afferent neurons (FIG. 1) and on the dendrites ofpost-synaptic neurons. MOP has the widest distribution in the CNS, andis thus the most important opioid receptor for pain management.Activation of the opioid receptor leads to inhibition of thevoltage-gated (voltage-dependant) calcium channels, as shown in FIG. 2,and stimulation of potassium efflux. (M. Stillman, Clinical Approach toPatients With Neuropathic Pain, Cleve. Clin. J. Med., 2006, 73 (8),726-739).

Perception of pain involves a complex array of networks from theviscera, skin and muscle to the spinal cord to the brain and back again.This integrated feedback of pain perception within the neuron involvesdynamic control of neurotransmitter release that is highly regulated(dynamic distribution ensemble). (A. J. Holdcroft, Core Topics in Pain,Cambridge University Press: United Kingdom, 2005). The crosstalk betweenthe different receptors on a particular neuron has been documented withrespect to opioid receptors and Ca channels. (H. Buschmann et al.,Analgesics: From Chemistry and Pharmacology to Clinical Application,Wiley-VCH: Federal Republic of Germany, 2002). Cross talk between thedifferent opioid receptors is further evidenced by dcx-receptor beingcomplexed with m-receptors and that sub-antinociceptive doses of[D-Pen²,D-Pen⁵]enkephalin (DPDPE) potentiated m-receptor-mediatedanalgesia. At higher doses DPDPE acted as an agonist at thedncx-receptor and induced analgesia. (A. Corbett et al., OpioidReceptors, http://opioids.com/receptors/index.html).

There is evidence to suggest that voltage dependant calcium channels area critical component of development of opioid tolerance and dependence.MOP, DOP and KOP mediate the calcium channels and blocking them withopioids will dampen the first order electrochemical impulse. Opioiddosage can be reduced without affecting analgesia by co-administering aCa channel blocker. (Buschmann, Id.) Thus, the activity and contributionto transmission or blocking of pain signals from Ca channels and opioidreceptors, particularly MOP, is dependant on the relative kinetics ofeach part of the neuron.

Since Ca channels and opioid receptors are interrelated kinetically, itstands to reason that this type of kinetically dependant cross talkwould occur intersynaptically, as well as intrasynaptically. Indeed, ithas been proposed that combining a Ca channel blocker with a MOP agonistin a single molecule would have excellent pharmacologic properties.(Buschmann, Id) In addition, this cross talk has been shown to beadvantageous in reducing tolerance and dependence by combining a MOPagonist with a DOP antagonist. (S. Ananthan, Opioid Ligands with MixedMu/delta Opioid Receptor Interactions: An Emerging Approach to NovelAnalgesics, AAPS J, 2006, 8 (1), E118-25). MOP, DOP and KOP have highdensity of these receptors in the dorsal horn (DH), where modulation ofN-methyl-D-aspartic acid (NMDA) receptor activation occurs. (Holdcroft,Id.). It is apparent that the dynamic distribution ensemble is a verycritical component of pain signaling in the DH; central sensitization,therefore, is that part of pain management where synergy betweendifferent methods of analgesia can best be enhanced. This is supportedby evidence that suggests that sensitization can only be partlyexplained by the changes in the periphery and that hyperalgesia andallodynia after injury has a central component. (A. B. Petrenko et al.,The Role of N-methyl-D-aspartate (NMDA) Receptors in Pain: A Review,Anesth Analg, 2003, 97 (4), 1108-16).

Acute morphine administration has been shown to have a variety ofprofound effects on many other neurotransmitters; this group comprisesfast-acting neurotransmitters including excitatory amino acids such asglutamate and slower-acting neurotransmitters such as norepinephrine,epinephrine and serotonin, as well as, dopamine and a variety ofneuropeptides.

The state of activity of opioid receptors is a complex interactiondepending upon interactions with other intracellular mediators. Forexample, calcium calmodulin-dependant protein kinase II (CaMKII)mediates postsynaptic signaling by NMDAR. CaMKII is preferentiallylocated in pain-processing centers in the CNS, particularly the dorsalhorn. Another mediator, PKC, may mediate Ca²⁺-dependant inactivation ofNMDA receptor. The mediation by CaMKII contributes to the simultaneousblocking of MOP and NMDA-R, which reduces the threshold amount ofglutamate released. This, in turn, reduces the amount of NMDA-Rantagonist required. In addition, blocking of the NMDA-R signal dampensthe overall nociception making the opioid more effective. Sincemediators are influenced by kinetic factors, potentiation depends on therelative kinetics of receptor blocking and activation, particularlyactivation of MOP.

Pain therapeutic targets include inflammation reduction, ion channelblocking and signaling pathway modulation. Treatment of pain derivingfrom the dynamic distribution ensemble view warrants multipletherapeutic interventions, incorporating one of the therapeutic targetsor combinations thereof. For example, intrathecal magnesium extended theduration of fentanyl analgesia. (A. Buvanendran et al., IntrathecalMagnesium Prolongs Fentanyl Analgesia: A Prospective, Randomized,Controlled Trial, Anesth Analg, 2002, 95 (3), 661-6). As anotherexample, morphine anti-nociception was potentiated by pentobarbital. (R.M. Craft & M. D. Leitl, Potentiation of Morphine Antinociception byPentobarbital in Female vs. Male Rats, Pain, 2006, 121 (1-2), 115-25).Third, activation of phsopholipase-A2 (PLA2) is linked to activation ofvoltage-sensitive potassium conductance, which explains the synergybetween opioids and NSAID's (Corbett, Id.).

Interestingly, there are limitations to opioid potentiation methods. Forexample, the non-steroidal anti-inflammatory drug (NSAID), ibuprofen,potentiates hydrocodone and oxycodone but not morphine or fentanyl.Similar limitations have been observed with NMDA-R antagonists as well,where ketamine affected long term potentiation in combination withfentanyl but only if it is administered with fentanyl and prior tonociception in perioperative procedures. Conversely, dextromorphan andmemantine failed in clinical trials as adjunct therapy with opioidanalgesics. In addition, tetrahydrocannabinol and the opioid receptoragonist, piritramide, do not act synergistically in post operative pain.

NMDA-R antagonists, voltage-gated ion channel blockers and NSAID's,which include COX-2 inhibitors, are the most studied adjunct therapeuticclasses. (J. A. Kemp & R. M. McKernan, NMDA Receptor Pathways as DrugTargets, Nat. Neurosci., 2002, 5 Suppl, 1039-42; A. R. Campos et al.,Ketamine-induced Potentiation of Morphine Analgesia in Rat Tail-flickTest: Role of Opioid-, Alpha2-adrenoceptors and ATP-sensitive PotassiumChannels, Biol. Pharm. Bull., 2006, 29 (1), 86-9; C. R. Lin et al.,Antinociceptive Potentiation and Attenuation of Tolerance by IntrathecalElectric Stimulation in Rats, Anesth. Analg., 2003, 96 (6), 1711-6; T.J. Schnitzer, Pain Management Today—Optimising the Benefit/risk Ratio:Defining the Role of Weak Opioids and Combination Analgesics, Clin.Rheumatol., 2006, 25 Suppl 1, S1; J. S. Kroin et al., Cyclooxygenase-2Inhibition Potentiates Morphine Antinociception at the Spinal Level in aPostoperative Pain Model, Reg. Anesth. Pain Med., 2002, 27 (5), 451-5).Yet there are other approaches to pain therapy that may also be used asadjunct therapies with opioid analgesics, which include 1) acetylcholinereceptor agonists, 2) adenosine neurotransmitters, 3) P2 receptorantagonists, 4) cannabinoids, 5) vanilloids and the VR1 receptoragonists, 6) substance P and the NK receptor antagonists, 7)CGRP₁-receptor antagonists, 8) nitric oxide, 9) antidepressants, 10)anticonvulsants, 11) alpha-2 adrenergic agonists and 12) GABA agonists.(Holdcroft, Id.; Buschmann, Id.; J. F. Wilson, The Pain Divide BetweenMen and Women, Ann. Intern. Med., 2006, 144 (6), 461-4; P. Lyden & N. G.Wahlgren, Mechanisms of Action of Neuroprotectants in Stroke, J. StrokeCerebrovasc. Dis., 2000, 9 (6 Pt 2), 9-14; J. S. Kroin et al., ClonidineProlongation of Lidocaine Analgesia After Sciatic Nerve Block in Rats isMediated Via the Hyperpolarization-activated Cation Current, Not byAlpha-adrenoreceptors, Anesthesiology, 2004, 101 (2), 488-94.)

Pharmacokinetics is a critical component of the efficacy of any drug.Some of the limitations associated with synergistic application ofanalgesic reagents could very well be due to the relativepharmacokinetics of the respective analgesic agents. Certainly thedynamic distribution ensemble view and the importance of cross talkbetween neurotransmitters and receptors support this premise. It is anembodiment of this invention, therefore, that by pharmacokineticallycontrolling the administration of receptor antagonists,neurotransmitters, receptor agonists, or anti-inflammatory agentsrelative to opioid analgesics, that maximum synergy between the twocomponent analgesics will be accomplished. It is a further embodiment ofthis invention that this maximum synergy will result in lower dosingrequired for both components, thus delaying tolerance and perhapsavoiding addiction and side effects associated with the adjunctanalgesic.

Opioid tolerance is clearly a heterogeneous syndrome where no one singlemechanism or loci is entirely responsible. Down regulation of opioidreceptors is believed to be a contributing factor to opioid tolerance.(D. E. Keith et al., Mu-Opioid Receptor Internalization Opiate DrugsHave Differential Effects on a Conserved Endocytic Mechanism in Vitroand in the Mammalian Brain, Mol. Pharmacol., 1998, 53 (3), 377-84).Up-regulation of the entire cAMP pathway in the locus ceruleus, which isbelieved to be the primary site for opioid physical dependence, may alsocontribute to tolerance. (E. J. Nestler & G. K. Aghajanian, Molecularand Cellular Basis of Addiction, Science, 1997, 278 (5335), 58-63).Multiple other neurotransmitter systems have been implicated in opioidtolerance. Rebound adenylyl cyclase activity in withdrawal may be afundamental step in eliciting the withdrawal behavior. (H. O. Collier etal., Quasi Morphine-abstinence Syndrome, Nature, 1974, 249 (456),471-3). Combining analgesia with antagonists has been proposed to reducetolerance. One could add a small amount of a potent analgesic, such asetorphine, with an antagonist to provide analgesia without tolerance.(Corbett, Id.) Chronic administration of opioid antagonists, primarilynaltrexone, will cause a significant up-regulation or increase indensity of MOP. (E. M. Unterwald et al., Quantitative Immunolocalizationof Mu Opioid Receptors Regulation by Naltrexone, Neuroscience, 1998, 85(3), 897-905).

Opiates appear to enhance dopaminergic tone and through that enhancementachieve some, most, or all of their reinforcing or rewarding effects.Cocaine caused a striking increase in extracellular dopamineconcentrations in the nucleus accumbens, and moreover the combination ofcocaine and heroin caused a synergistic elevation. (S. E. Hemby et al.,Synergistic Elevations in Nucleus Accumbens Extracellular DopamineConcentrations During Self-administration of Cocaine/heroin Combinations(Speedball) in Rats, J. Pharmacol. Exp. Ther., 1999, 288 (1), 274-80).Acute and chronic morphine administration increases neuroplasticity,which is mediated in part though action of dopamine D1 receptors. (M. J.Kreek, Molecular and Cellular Neurobiology and Pathophysiology of OpiateAddicition, Neuropsychopharmacology: The fifth Generation of Progress,2002, 1491-1506). Interfering with the rapid changes in the dopaminergictone, perhaps with dopamine receptor blocker, may prevent some of theopiate drug dependency.

It is an embodiment of this invention that an FMDD ligand be selectedfrom the group consisting of adjunct therapeutic agents listed above,which include NMDA-R antagonists, voltage-gated ion channel blockers,NSAID's, acetylcholine receptor agonists, adenosine neurotransmitters,P2 receptor antagonists, cannabinoids, vanilloids, VR1 receptoragonists, substance P, NK receptor antagonists, CGRP₁-receptorantagonists and nitric oxide. It is a preferred embodiment of thisinvention that an FMDD ligand be selected from the group consisting ofNMDA-R antagonists, voltage-gated ion channel blockers and NSAID's. In amost preferred embodiment of this invention an FMDD ligand is an NMDA-Rantagonist.

Infusion with low dose receptor antagonists potentiates analgesia byopioids. Delivering receptor antagonists with opioid concertedly willreduce the dosing requirement for each component and may even obviatethe need to infuse the receptor antagonist or the opioid.

The potentiation of receptors that are intrinsically linked occursthrough a mechanism that relies on the relative kinetics of thebiologically active moieties binding to their respective receptors.(Psychological and Physiological Consequences of NoncompetitiveAntagonsim of the NMDA Receptor by Ketamine:http://sulcus.berkeley.edu/mcb/165_(—)001/papers/manuscripts/_(—)819.html).So, when two moieties, such as an analgesic and an adjunct reagent, areintroduced into the body, their relative migration rates to theirrespective target receptors may not be coincident with the cross talkrequired for potentiation to occur. (G. Sathyan et al., The Effect ofDosing Frequency on the Pharmacokinetics of a Fentanyl HClPatient-controlled Transdermal System (PCTS), Clin. Pharmacokinet.,2005, 44 Suppl 1, 17-24). Therefore, potentiation through synergisticapplication of two or more biologically active agents involves a kineticcomponent that, if not incorporated into the drug design, may reduce oreliminate the effect altogether.

The respective receptors are linked by more than just chemistry; thereis a frequency component that facilitates the cross talk between thereceptors. Potentiation of the receptors is best achieved if thebiologically active moieties reach their respective receptors in amanner that closely matches the kinetics of the cross talk between thereceptors. Given that the time course of delivery to the targetreceptors will likely be different for the two moieties, it is alsolikely that the timing of the attachment to their receptors will notmatch the frequency of the cross talk. Delivery of the two moieties asligands in a single molecular entity is a viable method to modulate thefrequency of drug delivery.

For example, when the DOP antagonist, 7′-aminonaltrindole, and the MOPagonist, oxymorphamine, were linked with a hexyldiamine glycolate spacer(FIG. 3) it was found to be more potent than morphine and to produce notolerance or physical dependence. (Ananthan, Id.) It is an embodiment ofthis invention that the synergy between two analgesic agents ismaximized when combined in a single molecular entity.

In the above example the length of the linker was critical and,therefore, it may be difficult to optimize potentiation because of thetrial and error associated with linker chain length. Metal coordinationrepresents a viable alternative. The two ligands are still part of thesame molecule and the complex is designed such that it is stable in thebody until another biological entity strips one of the ligands away fromthe complex. The receptor for the stripped-away ligand could be thatentity. The metal:ligand complex that is still intact is then availablefor binding to the other receptor with or without the metal involved(FIG. 4). The migration distance between the receptors is much shorterthan the migration distance from the point of administration to thereceptors and, therefore, frequency modulation of drug delivery willmore likely match the frequency of the cross talk when the biologicallyactive moieties co-exist as ligands in a single molecular entity andespecially when the single molecular entity is bound together as a metalcoordinated complex.

In a preferred embodiment of this invention two analgesic agents areselected from the group of NMDA-R antagonists and MOP. Due to specificlimitations, in a most preferred embodiment of this invention, ketamineand fentanyl will affect long term potentiation if administered as asingle molecular entity.

In certain instances delivering the opioid agonist and an NMDA-Rantagonist as a single molecular entity may prevent the interaction ofthe neurotransmitter with the respective receptor. Many of the analgesicagents mentioned in this document have metal binding capacity. Additionof other stabilizing ingredients or components to the analgesic-metalcomplex will serve to stabilize the entire complex further. The FMDDcomplex is designed such that it should be stable enough to survive inthe body until it reaches its target organ. If an FMDD ligand is one ofthe adjunct analgesics discussed earlier, then its role would be toenhance the effect of the analgesic, particularly one of the opioids, aswell as stabilize the complex. The complex stability is compromised onlywhen another ligand in the body displaces one or the other analgesicligands attached to the metal. A receptor for one or the other analgesicligands will provide the thermodynamic impetus to dissociate thecomplex. Once the complex is broken down by the receptor, the otheranalgesic reagent is then free to migrate to its respective receptor.Thus the FMDD potentiation cycle is complete.

Many receptor-evoked cellular responses are known, some of which areinvolved in mediating the action of other receptors (e.g., inhibition ofadenylyl cyclase is linked to tolerance and potentiation of NMDAcurrents), and examination of these cellular functions may assist in anFMDD analgesic. K-agonists may also be useful in FMDD, such as6,7-benzomorphans, since they bind to other opioid receptors but showpreference for the k-receptor. A new class of opioid agonists based onenkephalin-mimics, in which a lead compound is actually the 6,7-indoleanalogue of naltrexone, naltrindole, may also provide some usefulcompounds for FMDD (Corbett, Id.).

In addition to the three well-defined classical opioid receptors, DOP,MOP and KOP, an orphan receptor, ORL-1, has been described, as well. TheORL-1 receptor also has selective agonists, antagonists of it are notwell known and therefore designing a drug that binds to both the ORL-1receptor and the m- or d- receptor may provide analgesic potentiationwithout causing tolerance or dependence.

Based on the stability and the dissociation mechanism of an FMDDligand:metal:opioid complex, it is an embodiment of this invention thatthe complex provides enhanced analgesic effect as a single molecularentity, thereby delivering both analgesics in a pharmacokineticallysynergistic manner. It is a further embodiment of this invention that bydelivering the analgesic agents as a single molecular entity thatenhanced synergy between the reagents is achieved in accordance with thedynamic distribution ensemble view. Furthermore, the enhanced analgesiceffect will reduce the dosage required from the opioid and thus reducetolerance and dependency. In a preferred embodiment of the invention anFMDD ligand analgesic is an NMDA receptor antagonist. Since magnesium isinvolved in the pathway leading to the hyperexcitable state and thataddition of magnesium can mimic the effects of NMDA receptor antagonistsit is a preferred embodiment of the invention that the metal used tocomplex the analgesic agents be magnesium. (S. Begon et al., MagnesiumIncreases Morphine Analgesic Effect in Different Experimental Models ofPain, Anesthesiology, 2002, 96 (3), 627-32).

It is preferable that the FMDD ligand have metal chelating properties,which in addition to forming a strong bond with the metal can also havethe capacity to stabilize the opioid-metal complex in accordance to theprincipals outlined earlier. The agents that make the best candidatesfor complexing with magnesium and calcium are those that have a protonon a heteroatom (i.e., oxygen, nitrogen or sulfur) with a pK_(a)slightly greater than water or less and have an additional heteroatom inclose proximity to the first protonated heteroatom such that it canparticipate in the bonding, or otherwise chelate, with the metal.Compounds that have this arrangement of functional groups are mostlikely going to bond with a metal, where the resultant metal coordinatedactive agent will be stable enough in a biological system and survivehydrolysis therein until the complex reaches the target site. In thisway, the FMDD ligand and the opioid analgesic will be delivered to thetarget receptor sites concurrently where the complex will dissociate andeach reagent will than impart its respective pharmacologic response.Because the responses are kinetically linked, the synergistic analgesia,with the attendant reduction in tolerance and dependency, is optimized.

Several NMDA receptor antagonists in varying stages of development, suchas ARL 15896AR and remacemide, meet the chelating criteria. Many of theglycine site antagonists undergoing preclinical evaluation, includingACPC, ACEA1328 and ZD9379, are good chelators as well. (C. G. Parsons,NMDA Receptors as Targets for Drug Action in Neuropathic Pain, Eur. J.Pharmacol., 2001, 429 (1-3), 71-8). The opioid narcotic is selected fromthe group consisting of morphine, morphine-6-glucuronide (M6G),oxymorphone, oxycodone, hydromorphone, codeine and hydrocodone. Amongstthe opioid narcotics in the selected group, perhaps the molecularstructure of morphine-6-glucuronide (M6G) is best suited forcomplexation with a metal. Therefore, it is a preferred embodiment ofthe invention that the complex is ARL15896AR:magnesium:M6G. Hydroxamicacids have shown remarkable stability as metal complexes and, therefore,it is an embodiment of this invention that an opioid analgesic beselected from a group of morphine-6-glucuronide hydroxamic acid (M6GHA), the metal coordinated analogs and FMDD analogs. Therefore, it is apreferred embodiment of the invention that the complex isARL15896AR:magnesium:M6 GHA. A most preferred embodiment of theinvention is remacemide:magnesium:M6 GHA complex shown in FIG. 12.

In a typical application, the metal complex is formulated foradministration and delivered orally or intrathecally. The analgesiceffect will have the usual pharmacokinetics, except the dosing isexpected to be less than with an opioid alone. The closer to the targetsite the complex can be delivered the better the probability that thecomplex will be stable until reaching the target site. Therefore, in apreferred embodiment of the invention FMDD ligand:metal:opioid complexis infused intrathecally.

Use in Treatment of Migraine Headaches

Migraine is a neurological disorder characterized by episodes of oftensevere, usually one-sided, frequently throbbing or pounding pain,associated with other features, such as nausea or vomiting, sensitivityto body movement, sensitivity to light, or sensitivity to sound,Triptans, 5-HT_(1B/1D) agonists that target the trigeminovascular systemand include marketed products such as sumatriptan, rizatriptan andzolmitriptan, are well established agents in treating the painassociated with migraines. 5HT receptors are one of the post-synapticdorsal horn projection neurons and 5HT (aka serotonin) is one keyneurotransmitter responsible for pain modulation at each levelthroughout the entire body. Serotonin also causes extravasation ofplasma proteins and hyperalgesia. Subtype 5HT receptors are localized tonociceptors and mediate peripheral effect of serotonin duringinflammation. The triptan molecules effectively block theserotonin-mediated synaptic transmission between the nociceptor and thecentral neuron in the dorsal horn.

Treximet is a combination of sumatriptan with the NSAID, naproxensodium, and provides support to the premise that combining twomedications can provide more effective relief of pain than using eitherdrug alone. Although the reasons for this have not been made clear bythe innovators of Treximet, it is likely due to potentiation of the twodrugs. It is therefore an embodiment of this invention that a triptan'sand an NSAID's potentiating effect can be optimized if the two drugs aredelivered to the respective targeted sites synergistically. It is afurther embodiment of this invention that delivering the two drugs as ametal coordination complex is a very effective way to optimize thispotentiation. In a preferred embodiment of this invention, the triptanin the metal coordination complex is sumatriptan and the NSAID isnaproxen. Since magnesium also possesses anti-migraine properties, amost preferred embodiment of this invention is(sumatriptan)(naproxen)magnesium. It can therefore be demonstrated thatin some applications the chelating metal itself may actually play a rolein the pharmacodynamics of the FMDD complex.

Krymchantowski, et. al. have reviewed the most current thinking on thefuture of the treatment of headaches and many of the same adjuncttherapies with opioid analgesics have also been implicated as possiblemodes of action for the treatment of migraines. (A. V. Krymchantowski etal., The Future of Acute Care and Prevention in Headache, Neurol. Sci.,2007, 28 Suppl 2, S166-78). A literature summary of alternative methodsof treating headaches and migraines include:

-   1) Topiramate influences the action of some types of voltage-gated    sodium and calcium channels, GABA_(A) receptors the AMPA/kainate    subtype glutamate receptors.-   2) Tiagabine inhibits neuronal and glial uptake of GABA-   3) Zonisamide blocks voltage-dependant sodium channels, reduces    glutamate-mediated exicitatory neurotransmission, inhibits excessive    nitric oxide production, scavenges hydroxyl radicals and inhibits    carbonic anhydrase.-   4) Carvedilol has antioxidant properties.-   5) Tizanidine inhibits the release of norepinephrine in the    brainstem.-   6) Quetiapine has a high affinity for 5-HT₂ receptors.-   7) Adenosine neurotransmitters exhibit both chronic and acute    analgesic properties-   8) Vanilloids and the VR1 receptor agonists, such as capsaicin and    civamide, leads to rapid desensitization, loss of sensitivity to    heat and chemical stimulation.-   9) Substance P, CGRP₁-receptor and the NK receptor antagonists block    neuronal transmission and inflammation.-   10) Calcitonin gene-related peptide (CGRP) is thought to have an    important role in the pathophysiology of migraines and is currently    a new class of migraine drug in clinical trials (e.g. BIBN 4096 BS).-   11) Nitric oxide is released in conjunction with CGRP from nerve    terminals triggering the migraine cascade.-   12) COX increases nociceptive thresholds and causes tenderness.

Thus it is an embodiment of this invention that any two or more of theagonists or antagonists listed above can be combined as a metalcoordination complex such that the biological agents will be deliveredto their respective receptors with the kinetic synergy necessary toachieve potentiation of said biological agents in accordance with theprinciples described in this invention.

Use in Treatment of Neurodegenerative Diseases

Parkinson's Disease

Parkinson disease is characterized by loss of motor function control dueto degeneration of the dopaminergic neurons and of other neurons in themonoaminergic family in the midbrain. The most prominent neuronal lossoccurs in the substantia nigra, which leads to depletion of dopamine inthe striatum causing an imbalance between the dopaminergic andcholinergic systems. The resultant excessive release of the inhibitoryneuro-transmitter, gamma aminobutyric acid (GABA), leads to theparkinsonian motor dysfunction that characterizes the disease. (M. DiNapoli et al., Molecular Pathways and Genetic Aspects of Parkinson'sDisease: From Bench to Bedside, Expert Rev. Neurother., 2007, 7 (12),1693-729).

Treatment for the resulting motor dysfunction associated with Parkinsondisease typically consists of agents that replace dopamine, mimicdopamine activity, or increase dopamine availability in the centralnervous system. (J. Rao, Advances in Treatment of Parkinson Disease,Evolving Concepts in Parkinson Disease Pathophysiology, Diagnosis, andTreatment, 2007, 10-13). Maintaining consistent carbidopa-levodopaplasma levels presents a challenge in the treatment of Parkinson diseaseand results in periods of “off” times, which may require patients totake multiple doses throughout the day. As the disease progresses,adjunctive therapy or additional carbidopa-levodopa doses to minimize ortreat the increases in symptomatic “off” time between levodopa doses isusually required. (M. Tagliati, Carbidopa-Levodopa Oraly DisintegratingTablets, Evolving Concepts in Parkinson Disease Pathophysiology,Diagnosis, and Treatment, 2007, 7-9). Furthermore, although levodopaprovides dramatic relief of PD symptoms, prolonged treatment leads to avariety of adverse motor and cognitive effects. (M. J. Marino et al.,Glutamate Receptors and Parkinson's Disease: Opportunities forIntervention, Drugs Aging, 2003, 20 (5), 377-97).

The later stages of idiopathic Parkinson's disease (IPD) arecharacterized by a decline in response to levodopa and motorcomplications such as dyskinesias and response fluctuations. (C. E.Clarke et al., T. A., A randomized, Double-blind, Placebo-controlled,Ascending-dose Tolerability and Safety Study of Remacemide as AdjuvantTherapy in Parkinson's Disease with Response Fluctuations, Clin.Neuropharmacol., 2001, 24 (3), 133-8). Throughout the progression of thedisease, under chronic conditions of enhanced neuronal susceptibilityglutamate's lethal action impacts the efficacy of the dopaminergicdrugs. (G. C. Palmer, Neuroprotection by NMDA Receptor Antagonists in aVariety of Neuropathologies, Curr. Drug Targets, 2001, 2 (3), 241-71).

There are a host of neurologic disorders that share the classic symptomsof Parkinson disease. Diagnosis for the disease can sometimes be trickyas shown in Table 2. Progressive supranuclear palsy (PSP) and multiplesystem atrophies (MSA) are examples of neurodegenerative diseases withparkinsonian features. (A. Nicholas, Pathophysiology and Diagnosis ofParkinson Disease, Evolving Concepts in Parkinson DiseasePathophysiology, Diagnosis, and Treatment, 2007, 1-4).

TABLE 2 Differential Diagnosis of Parkinson Disease Common MisdiagnosisDistinguishing Features Essential tremor Tremor (action, postural), noresponse to PD drugs Progressive Supranuclear palsy, upright posture,pseudobulbar supranuclear palsy affect, early gait instability, numerousfalls, dysphagia, rarely responds to PD drugs Multiple system Autonomicdisturbance, cerebellar signs, relative atrophy absence of tremor, earlygait instability, dysphagia Corticobasal Limb apraxia, cortical sensoryabnormalities, degeneration early dementia, alien limb, rarely respondsto PD drugs Diffuse Lewy body Early dementia, psychosis, agitationdementia Alzheimer disease Dementia is the primary symptom Drug-inducedExposure to dopamine-blocking drugs, relative parkinsonism lack of resttremor and asymmetry, can be reversible Vascular parkinsonism History ofchronic hypertension, stepwise progression (if any), unilateral, imaginerelative absence of tremor

The pathophysiology of Parkinson's disease involves a very complex arrayof receptors and neurons in the basal ganglia, which are a set ofinterconnected subcortical nuclei partly responsible for control ofmotor behavior. (Marino, Id.) The current understanding of theinformation flow in the basal ganglia is that output from the substantianigra pars compacta (SNc) is both critical to striatum function and isimpacted by a complex set of signals in other components of the circuit.The proper function of the basal ganglia consists of signals that aretransferred through its different structures and are typified byinhibitory GABAergic, excitatory glutamatergic and dopaminergic signals.(FIG. 13 a).

Both the loss of striatal dopamine output and the increased excitatoryglutamatergic drive through the indirect pathway are implicated ascausative factors in PD patients. (FIG. 13 b) These effects create animbalance between direct inhibition and indirect excitation of the basalganglia output nuclei, which is crucial for control of normal motorbehavior, and alterations in this circuit underlie a variety of movementdisorders including PD. (Marino, Id.)

The glutamatergic drive causes glutamate/glycine interactions to releaseMg⁺² from the receptor site into the cytosol, thereby allowing passageof calcium through the ion channel into the cell. This ion channel isfurther controlled by the NMDA receptor that can trigger calcium influxbut only when the ion channel is open. This causes the release of excessamounts of glutamate and the resultant receptor-operated calcium fluxinto the cell may be of sufficient magnitude as to be lethal to neurons.(Palmer, Id.) The whole pathophysiology of PD is self exacerbatingbecause excessive excitatory drive through the indirect pathwayunderlies the increase in basal ganglia outflow, which is believed to beresponsible for further neurodegeneration of SNc neurons. (Marino, Id.)Further, abnormal accumulation of iron and copper in the brain has beenassociated with the development of PD and other neurodegenerativedisorders.

It is not surprising then that secondary disruptions in theglutamatergic system are responsible for many of the motor symptoms ofPD and, therefore, the glutamatergic system has been the focus forproviding several potential targets for novel intervention in PD(Marino, Id.).

There are studies that show that the basal ganglia complex haveinterconnected receptors that crosstalk much in the same way that otherCNS receptors do. (Klopman, et. al.) demonstrated the in silicoeffectiveness of compounds bearing pharmacophores of MAO-B inhibitors,dopamine agonists and NMDA antagonists; theoretically combining thesepharmacophores into a single molecular entity could synergisticallyenhance their antiparkinson effect. (G. Klopman & A. Sedykh, An MCASEApproach to the Search of a Cure for Parkinson's Disease, BMCPharmacol., 2002, 2, 8). One could envision extrapolating from thepharmacophore combination principals in this paper by performing thesame function but retaining the entire integrity of the molecule toensure optimum pharmacologic effect. Thus it is an embodiment of thisinvention that pharmacophores on antiparkinson's drug can be combined asa single molecular entity by complexing each of the drugs to a metal.

The NMDA receptor plays a key role in many neurophysiologic functionsincluding neurotransmission through a complex set of modulatory siteslocated on the NMDA receptor. These functions are integrated with otherneurotransmitter systems through a variety of mechanisms involving themodulation of NMDA receptor currents. (Marino, Id.)

Agonist binding to the NMDA receptor allows high calcium ion flux, whichcontributes to synaptic plasticity, development and degeneration. TheNR2B subunit selective and the high and low affinity use-dependent NMDAantagonists exert their dynamic control of calcium entry into theneuron. (Palmer, Id.) A key component to the NMDA receptor's synergisticneurotransmission is the role that magnesium plays in the calcium flux.In the resting state magnesium blocks the ion channel, which imparts astrong voltage dependence to the channel. This allows the NMDA receptorto act as a coincidence detector, which requires participation fromglutamate and glycine, and postsynaptic depolarization before conductingcurrent. (J. Z. Tsien, Linking Hebb's Coincidence-detection to MemoryFormation, Curr. Opin. Neurobiol., 2000, 10 (2), 266-73; P. H. Seeburget al., The NMDA Receptor Channel: Molecular Design of a CoincidenceDetector, Recent Prog. Horm. Res., 1995, 50, 19-34).

There have been many reports on the complex interactions between theNMDA receptors and the glutamate system in the striatum. For example,intrastriatal injections of both competitive and noncompetitive NMDAantagonists was shown to induce an increase in locomotor behavior thatis mediated by a mechanism involving the D1 subtype of dopaminereceptors. (M. Morelli et al., Opposite Effects of NMDA ReceptorBlockade on Dopaminergic D1- and D2-mediated Behavior in the6-hydroxydopamine Model of Turning: Relationship with c-fos Expression,J. Pharmacol. Exp. Ther., 1992, 260 (1), 402-8). Examples of D1 subtypereceptor agonists of which would potentially be a component of the FMDDcomplex include the catecholamines (e.g. apomorphine, dihydrexidine,dinapsoline, dinoxyline and dopamine). Yet there are studies thatsuggest that competitive NMDA receptor antagonists actually increasedyskinesias. It is important to note here that this apparentcontradiction in NMDA receptor antagonists activity can be explained byspecies differences, differences in the extent of the MPTP-inducedlesion, and differences in the pharmacokinetic profile of the compoundsused (Marino, Id.). Moreover, the NMDA antagonist remacemide has beenobserved to enhance levodopa's effects in stimulating locomotor activityin reserpinized rats. (J. T. Greenamyre et al., Antiparkinsonian Effectsof Remacemide Hydrochloride, a Glutamate Antagonist, in Rodent andPrimate Models of Parkinson's Disease, Ann. Neurol., 1994, 35 (6),655-61; Remacemide Information Summary:http://www.ninds.nih.gov/funding/research/parkinsonsweb/drug_summaries/remacemide.htm). A low dose of remacemide (5 mg/kg) administered with the lowesteffective dose of levodopa (75 mg/kg) was able to increase horizontalmotor activity significantly (9-fold) over that found with levodopagiven alone (2). Other studies also demonstrated the potentiated effectsof levodopa in animal models of Parkinson's disease when NMDAantagonists are added. (S. Kaur & M. S. Starr, Differential Effects ofIntrastriatal and Intranigral Injections of Glutamate Antagonists onMotor Behaviour in the Reserpine-treated Rat, Neuroscience, 1997, 76(2), 345-54).

Thus, it is an embodiment of this invention that optimum pharmacologicresponse of an NMDA receptor antagonist can be attained when itssynergistic effect is pharmacokinetically controlled. It is a furtherembodiment of the invention that this pharmacokinetic control isaccomplished by complexing the NMDA receptor antagonist and thedopaminergic drug to a metal.

Given the complex network of neurons, receptors and neurotransmitters inthe basal ganglia responsible for motor control it is not surprising tolearn that several classes of receptor antagonists have been studied asa treatment for PD and other related disease states. For exampledopamine receptor agonists, MAO-B inhibitors and NMDA receptorantagonists are all known to have antiparkinson effects. (S. Isaacson,Current Medical Treatment of Parkinson Disease, Evolving Concepts inParkinson Disease, Pathophysiology, Diagnosis, and Treatment, 2007,4-6). In addition studies have demonstrated the benefit of NMDA receptorantagonists in the reducing levodopa-induced dyskineasias (Clarke, Id.).

Other classes of compounds affecting the NMDA receptor, are thesubunit-selective antagonists acting at the glycine site, allostericinhibitors at the polyamine site, and inhibitors of glutamate release(Marino, Id.; M. Ankarcrona et al., Glutamate-induced Neuronal Death: ASuccession of Necrosis or Apoptosis Depending on Mitochondrial Function,Neuron., 1995, 15 (4), 961-73; S. A. Lipton, S, Prospects for ClinicallyTolerated NMDA Antagonists: Open-channel Blockers and Alternative RedoxStates of Nitric Oxide, Trends Neurosci., 1993, 16 (12), 527-32; D.C.D'Sousa & John Krystal, Clycine Site Agonists of the NMDA Receptor: AReview, CNS Drug Reviews, 1995, 1 (2), 227-260.) Glutamate acts on twoclasses of receptors, the ionotropic glutamate receptors (iGluRs) andthe metabotropic glutamate receptors (mGluRs). Both the iGluRs and themGluRs are potential targets for the treatment of PD. It is of interestto note that mGluR5 plays a role in the facilitation of burst firing inthe STN and presynaptic mGluRs may play an important role in regulatingthe excitatory input to the basal ganglia thus mGluRs antagonists may beideal candidates for FMDD synergy with other drugs to provideantiparkinsonian effects (Marino, Id.).

Multiple studies have found that structurally diverse AMPA antagonistssynergize with levodopa or direct dopamine agonists to produce increaseturning behavior or reversal of akinesia in 6-OHDA-lesioned rats. Thedecrease in effectiveness to repetitive levodopa treatments observed inrodent models is completely blocked by combining an AMPA antagonist withlevodopa (Marino, Id.).

Other classes of receptor agonists and antagonists that may be suitablecandidates for FMDD treatment of PD are kainic acid and metabotropicreceptors linked to G-protein actions, anticholinergic agents andadenosine agonists. (C. G. Parsons et al., Glutamate in CNS Disorders asa Target for Drug Development: An Update, Drug News Perspect., 1998, 11(9), 523-69; A. Napolitano et al., New Directions in Parkinsons Researchand Treatment, Expert Opinion on Therapeutic Patents, 1998, 8 (10),1251-1268).

Perhaps the most well-known NMDA receptor antagonist is remacemide.Remacemide was originally described as a fast sodium channel blocker andhas previously been tested in clinical trials for epilepsy, stroke andAlzheimer's disease. (J. A. Kemp & R. M. McKernan, NMDA ReceptorPathways as Drug Targets, Nat. Neurosci., 2002, 5 Suppl, 1039-42; C.Missale et al., The NMDA/D1 Receptor Complex as a New Target in DrugDevelopment, Current Topics in Medicinal Chemistry, 2006, 6, 801-808).There was evidence that remacemide produced an improvement in patients'symptoms, particularly with regard to motor impairment. (Clarke, Id.)Remacemide is a safe and tolerable adjunct to dopaminergic therapy forpatients with Parkinson's disease and was found to potentiate theactions of levodopa. (S. Schwid, A Randomized, Controlled Trial ofRemacemide for Motor Fluctuations in Parkinson's Disease, Neurology,2001, 56, 455-462). Work with remacemide in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primatessuggested that its use in human patients with IPD may augment theclinical benefits seen with levodopa. (Greenamyre, Id.) It is anembodiment of this invention that combining DOPA with remacemide in ametal complex will provide the kinetic synergy necessary to furtheraugment the effects of both DOPA and remacemide as a treatment for PD,epilepsy, stroke and Huntington's disease.

Amantadine and its derivative memantine have been in clinical use of thetreatment of PD for over 30 years. Likewise, dextromethorphan anddextrorphan are weak NMDA antagonists that have exhibited some clinicalefficacy in alleviating levodopa-induced dyskinesias. (Marino, Id.)Rasagiline (Azilect) elicits a neuroprotective effect and is anirreversible, highly specific monoamine oxidase B (MAO-B) inhibitorapproved in the United States in May 2006 as monotherapy for patientswith PD or as an adjunctive therapy with levodopa. (Rao, Id.) The FDAapproved the Zydis formulation of selegiline (Zelapar), anotherirreversible selective inhibitor of MAO-B, in June 2006 as adjunctivetherapy for patients with a deteriorating response to levodopa. (E. V.Encarnacion & R. A. Hauser, Considerations in Neuroprotection inParkinson's Disease, Medscape Neurology and Neurosurgery, 2007).

The NMDA receptor antagonists, dizocilpine, CPP[(R,S)-3-(2-carboxypiper-azin-4-yl)-propyl-1-phosphonic acid] andbudipine, all potentiate the turning response induced by dopamineagonists in the 6-OHDA rat model. Budipine, a drug with a broad spectrumof action, is clinically useful in treating PD (Marino, Id.).

Development of a series of subunit-selective compounds related toifenprodil has emerged from studies of NMDA receptors. Both ifenprodiland traxoprodil have been found to be effective antiparkinsonian agentsin MPTP-lesioned primates. The AMPA antagonist NBQX (NNC079202) hasshown promise as an adjunct to dopamine agonists. The competitiveantagonists CPP an MDL 100453 [(R)-4-oxo-5-phosphononorvaline] have beenindicated as potentiators of levodopa (Marino, Id.).

Activation of group I mGluRs by the group I mGluR-selective agonist DHPG[(R,S)-3,5-dihydroxyphenylglycine] induces direct effects on GP neuronsincluding an inhibition of N- or P-type calcium conductances. Thepharmacology of this direct depolarization has been determined using themGluR1-selective antagonist LY367385[(S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid], and themGluR5-selective antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine].This depolarization is blocked by the mGluR5-selective antagonist MPEP,but not by the mGluR1-selective antagonist7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester(CPCCOEt), indicating that only one of the group 1 mGluRs (mGlueR5)localized at this synapse mediates the direct depolarization of theseneurons (Marino, Id.).

Dopaminergic neurons have increasing reliance on Ca²⁺ channels tomaintain their autonomous activity. This has been posited to becontributing factor to the degeneration of dopaminergic neurons observedin Parkinson's disease patients. In fact, calcium channel blockers havebeen found to force dopaminergic neurons to maintain autonomous activityin a Ca²⁺ independent manner. Moreover, the calcium channel blocker,isradipine, has been shown to provide neuroprotection against toxinsknown to illicit Parkinson's disease symptoms. (D. J. Surmeier, Calcium,Aging, and Neuronal Vulnerability in Parkinson's Disease, LancetNeurol., 2007; 6(10), 933-8). Therefore, it is an embodiment of thisinvention that combining levodopa with a calcium channel blocker in ametal complex will provide the kinetic synergy to further augment theeffects of both DOPA and the calcium channel blocker as a treatment forPD, epilepsy, stroke and Huntington's disease. It is preferredembodiment of this invention that the calcium channel blocker beselected from the class of drugs known as dihydropyridines. In a mostpreferred embodiment of this invention the dihydropyridine drug isisradipine.

Other specific examples of compounds that have shown to augment theactions of DOPA and thus are also candidates for FMDD as described aspart of the embodiment of this invention include SIB 1893[2-methyl-6-(2-phenylethenyl)pyridine], a selective mGluR5 antagoniststructurally related to MPEP, the highly selective group II mGluRagonist LY354740 (eglumegad), which was shown to decreasehaloperidol-induced muscle rigidity, the group II mGluR-selectiveagonist DCG-IV [(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine],which demonstrated a group II mGluR-specific reversal ofreserpine-induced akinesia when injected intranigrally and the iron andcopper chelating agents, carnosine and anserine. (Marino, Id.; J. H.Kang, Protection by Carnosine and Homocarnosine againstL-Dopa-Fe(III)-Mediated DNA Clevage, Bull. Korean Chem. Soc., 2005, 26(8), 1251-1254).

Inosine is a precursor of urate, which is deficient in PD patients andboth urate and inosine have been studied as possible treatments to slowthe progression of PD. Désirée Lie, Urate Slows Progression ofParkinson's Disease, Medscape Medical News, 2008. Creatine is also beenfound to slow the progression of PD. Thus, inosine, creatine and urateare also candidates for FMDD as described as part of the embodiment ofthis invention.

Alzheimer's Disease

A recent study found that memory loss due to degenerative braindiseases, including Alzheimer's, may be reversible with the help ofmental stimulation and use of drugs. The study (Nature), which wascarried out by researchers at the Massachusetts Institute of Technology(MIT), found that genetically engineered mice with a triggered proteinlinked to degenerative brain disease that resulted in an Alzheimer-likecondition were able to regain memories of tasks they had previously beentaught with the help of two methods: brain stimulation and drugs. Thedamage was inflicted in the mice through the specific neural networks inthe brain and the scientists achieved the same regenerative resultsthrough a drug treatment. The researchers also tested histonedeacetylase (HDAC) inhibitors on the mice, which seemed to improvememory and learning, similar to improvements made by environmentalstimulation. (A. Fischer et al., Recovery of Learning and Memory isAssociated with Chromatin Remodelling, Nature, 2007, 447 (7141),178-82).

It is yet to be determined if the same techniques would work in humansbut scientists are optimistic at the possibility of recovering long-termmemories in patients whose brains suffered certain neurologicaldisorders. Thus it seems that memories are not erased from the brain,but rather are made inaccessible by the disease.

While early high-affinity, uncompetitive NMDAR antagonists certainlycaused deterioration in Alzheimer's patients, lower-affinity, un- ornoncompetitive antagonists like memantine (and remacemide) have beenshown not to interfere with normal synaptic transmission and to actuallyimprove cognition in Alzheimer's patients while offering neuroprotectionagainst disease progression.

Proteins with expanded polyglutamine repeats are implicated in thetranscriptional dysfunction that is believed to be an importantpathogenic mechanism of many neurodegenerative diseases includingAlzheimer's. In particular the loss of function of the transcriptionalco-activator CREB-binding protein (CBP) is of particular note in theetiology of these diseases. It has been proposed that over-expression orloss of function of CBP will result in synaptic transmission defects.This seems to demonstrate that there is a critical balance required forCBP for proper synaptic transmission and that countering CBP binding(i.e. reduced acetylation of histones) with HDAC inhibition couldprovide the right balance of CBP activity. Recently it has been reportedthat the polyglutamine-containing domain of specific protein,Huntingtin, causes a reduction in the level of acetylation of histonesand that this effect can be reversed by administration of HDACinhibitors. (L. M. Thompson et al., Histone Deacetylase Inhibitors forReducing Polyglutamine Toxicity In vivo, Provisional PatentApplications, 2001).

Glutamic acid and aspartic acids are the physiological mediators of mostexcitatory synaptic transmission. The synaptic balance that is criticalfor proper regulation of polyglutamine is thus regulated by theseneurotransmitters. The NMDA receptors are a critical component ofmetabotropic glutamate receptors, responsible for increases in calciumand sodium fluxes. Intracellular calcium overload is one signal forneuronal death. In addition to polyglutamine, other mediators ofsynaptic transmission that operate on the NMDA receptor, such as nitricoxide, arachadonic acid, super oxide are also mediators of neuronaldeath. (R. J. Thomas, Excitatory Amino Acids in Health and Disease, J.Am. Geriatr. Soc., 1995, 43 (11), 1279-89). The entire synaptic balanceis influenced by all of these neurotransmitters and receptors,particularly the NMDA receptors, which interact with the expression ofgene products, of which CBP and, consequently HDAC, are intimatelyinvolved. Thus it stands to reason that a very effective application ofthis FMDD concept would be a combination of an NMDA receptor antagonistlike remacemide and an HDAC inhibitor like SAHA. Moreover, it has beenproposed that anti-CBP gene products that lead to apoptosis arepotentiated by highly active NMDA receptors. Thus it appears that HDACmediated gene products and NMDA receptors are intrinsically linked tothe etiology of Alzheimer's disease and related neurological disorders.

It is an embodiment of this invention, therefore, that anHDACi-metallo-NMDAR inhibitor complex provides potentiated treatment forAlzheimer's disease and related disease states beyond what theindividual components could. It is a further embodiment of the inventionthat SAHA-metal-remacemide represents a new combination of drugscombined to potentiate their respective efficacies in treatingAlzheimer's and related disease states. In a most preferred embodimentof the invention the FMDD drug complex is SAHA-Mg-remacemide.

L-methylfolate is being marketed for treatment of peripheral neuropathy,depression and Alzheimer's dementia by Pamlab. It is an NMDAR antagonistand easily crosses the blood brain barrier. Thus it is an embodiment ofthis invention that SAHA-metal-methylfolate represents a new combinationof drugs combined to potentiate their respective efficacies in treatingAlzheimer's and related disease states. In a most preferred embodimentof the invention the FMDD drug complex includes SAHA-Mg-methylfolate.

Carnosine (beta-alanyl-L-histidine) is a naturally-occurring dipeptidewhich, along with zinc, typically enriches the olfactory lobe. Carnosinehas been shown to suppress amyloid-beta peptide toxicity, inhibitproduction of oxygen free-radicals, scavenge hydroxyl radicals andreactive aldehydes, and suppress protein glycation, which may allcontribute to the pathophysiology of Alzheimer's Disease and otherneurodegenerative diseases. Further, zinc accumulation is a prominentfeature of advanced Alzheimer disease and has been linked to brainamyloid β-peptide aggregation and dementia severity.

It is thus an additional embodiment of this invention thatcarnosine-metal-HDACi, carnosine-metal-NMDAR inhibitor andcarnosine-metal-methylfolate FMDD drug complexes could synergisticallypotentiate the respective therapeutic utilities of these agents. Also,given the zinc-chelating properties of carnosine and that magnesiumitself effectively acts as an inorganic calcium-channel blocker andcould amplify NMDA receptor blockade, the most preferred embodiment ofthese additional inventions are carnosine-Mg-remacemide andcarnosine-Mg-methylfolate.

Epilepsy

A report of a combined treatment of the potent non-competitive NMDA-Rantagonist dizocilpine with valproate, which provided a 50% protectionagainst MES induced seizures, also produced a ˜3-fold reduction in theED₅₀ of valproate. In addition, some of the valproate-induced sideeffects could not be observed when the combination with valproate wasused. (B. K. Kohl & G. Dannhardt, The NMDA Receptor Complex: APromisingTarget for Novel Antiepileptic Strategies, Curr. Med. Chem.,2001, 8 (11), 1275-89).

Synergism between the polyamine site antagonist, eliprodil, and theglycine_(B) receptor antagonist, L-701,324, was observed in the amygdalakindling model in rats (Kohl & Dannhardt, Id.). Thus it is an embodimentof this invention that polyamine site antagonist and glycine_(B)receptor antagonists potentiate each other in accordance to the premiseof this invention through metal coordination. In a preferred embodimentof the invention the FMDD complex includes eliprodil-metal-(L-701,324).

Carnosine can protect against PTZ-induced seizures and acts mainlythrough the carnosine-histidine-histamine metabolic pathway. (Y. Y. Zhuet al., Carnosine Inhibits Pentylenetetrazol-induced Seizures byHistaminergic Mechanisms in Histidine Decarboxylase Knock-out mice,Neurosci. Lett., 2007, 416 (3), 211-6). Thus, carnosine, once more, isimplicated as a key FMDD ligand in potentiating the effects of drugsacting on the central nervous system. Nipecotic acid has also beentested on PTZ-induced convulsions in rats, and thus, is also a potentialFMDD ligand in the treatment of epilepsy.

Nearly 30% of epilepsy sufferers have seizures that are refractory tocurrently available drugs. In response to these refractory conditions,new anti-epileptic drugs, such as remacemide, are being developed. Inone study, remacemide inhibited glutamatergic transmission by blockingNMDA receptors while lamotrigine exerted preferential pre-synapticaction. Thus, coadministration of low doses of both drugs providedadditive neuroprotective properties. Moreover, in addition tolamotrigine, remacemide has been studied as a combination therapy withphenyloin, felbamate, gabapentin, oxcarbazepine, vigabatrin, zonisamideand valproic acid. FMDD-designed combinations of these agents arecontemplated by this invention. (P. Calabresi et al., Lamotrigine andRemacemide Protect Striatal Neurons Against In Vitro Ischemia: AnElectrophysiological Study, Exp. Neurol., 2003, 182 (2), 461-9; J. P.Leach et al., Mutual Interaction Between Remacemide Hydrochloride andPhenyloin, Epilepsy Res., 1997, 26 (2), 381-8; J. P. Leach et al., Lackof Pharmacokinetic Interaction Between Remacemide Hydrochloride andSodium Valproate in Epileptic Patients, Seizure, 1997, 6 (3), 179-84).

Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory autoimmune disease thatprogresses through demyelination and axonal loss in the brain and spinalcord. The etiology and progression of MS involves variouspathomechanisms, which include immune-related inflammatory cascade,oxidative toxicity and excitotoxicity. Moreover, the disease hasmultiple levels of damage, wherein destruction of myelin-producingoligodendrocytes follows a different pathology than the mechanisms thatmediate axonal and neuronal damage.

The pathogenesis of the disease is believed to be initiated by theantigen activation of autoreactive T lymphocytes, which afterpenetration through the BBB cause secretion of pro-inflammatorycytokines. The activity of these cytokines results in recruitment ofcirculating lymphocytes and monocytes and their transformation intomacrophages. This sets up a cascade of events including myelinphagocytosis, inflammatory signals and expression of apoptotic geneproducts, all of which lead to the damaging effects characterized by MS.Thus the beneficial effect of an MS drug can intervene anywhere in thiscascade of events including the application of anti-inflammatorymediators. (B. Weinstock-Guttman & R. Bakshi, Combination Therapy forMultiple Sclerosis: The Treatment Strategy of the Future?, CNS Drugs,2004, 18 (12), 777-92). For example, an agent that augmentsimmuno-modulation of myelin-reactive T cells toward Th2 differentiationcould be beneficial.

Therapeutic agents for the treatment of MS are typically focused on theimmune-mediated inflammatory cascade and oxidative toxicity. (R. E.Gonsette, Combination Therapy for Multiple Sclerosis, Int. M. S. J.,2004, 11 (1), 10-21). Acute symptomatic attacks and relapses followed byperiods of remission, also known as relapsing-remitting multiplesclerosis (RRMS), are typically treated with high-dose intravenoussteroids such as methylprednisolone which acts to dampen theinflammatory cytokine cascade, decreases the extravasation of activatedimmune cells into the central nervous system, suppresses the activationof destructive T-cells, and reduces the cytotoxic effects of nitricoxide and tumor necrosis factor. Disease modifying agents includevarious interferons, glatiramer acetate, mitoxantrone and natalizumab, ahumanized monoclonal antibody integrin antagonist. (Weinstock-Guttman,Id.) Fumaric acid esters have also been shown to inhibit activatedmacrophage migration, adhesion, and extravasation in MS patients withactive disease and may have a future role in chronic oral suppressivetherapy.

The strategies currently used for multidrug therapies in MS includefixed dose combination therapy for targeting distinct pathomechanisms orsequential addition of drugs to maintain or potentiate the efficacy ofthe first drug administered. These include concurrent use ofmethylprednisolone with immunosuppressive agents such as mitoxantroneand azathioprine, beta interferon (IFNβ) with glatiramer acetate, andIFNβ/natalizumab combination therapy (Gonsette, Id.). Oftentimes,however, these combinatorial strategies do not manifest theeffectiveness that is desired or manifest serious adverse side effectsthat may be due to the fact the administration of the MS drugs are notkinetically synergistic.

For example, by also altering the expression of adhesion molecules andpreventing leukocyte migration across the blood-brain-barrier, IFNβ maypotentiate natalizumab's antagonism of integrin within the CNS andreduce the inflammatory cascade leading to demyelination in refractorycases. This nonspecific and uncontrolled potentiation, however, may leadto the development of progressive multifocal leukoencephalopathy (PML)in these patients, an often fatal opportunistic viral disease. (H. H.Salama et al., Effects of Combination Therapy of Beta-interferon 1a andPrednisone on Serum Immunologic Markers in Patients with MultipleSclerosis, Mult. Scler., 2003, 9 (1), 28-31).

The premise of this invention is that by combining two or more MS drugsas a single molecular entity, effectively delivering therapies in a morecontrolled and discrete synergistic fashion, strategies addressingmultiple pathomechanisms can be more effectively designed andimplemented without problematic over-potentiation of targeted pathways.It is an embodiment of this invention, therefore, that combining two ormore drugs with a metal to form a single molecular entity metalcoordination complex has the proper FMDD properties to treat separatepathomechanisms associated with MS with the optimum kinetic synergy topotentiate the effects of the MS drugs that are a part of the metalcoordination complex.

It is additionally believed that IFNβ works on MS via itsanti-proliferative effects, suppression of pro-inflammatory cytokines,and the effects on matrix metalloproteinases. Glatiramer acetate isbelieved to inhibit specific effector T-lymphocytes and inducesuppressor T-lymphocytes, thus combining glatiramer acetate with IFNβfits with the multiple mechanistic approaches and has demonstrated anadditive effect in vitro. (M. J. Tullman & F. D. Lublin, CombinationTherapy in Multiple Sclerosis, Curr. Neurol. Neurosci. Rep., 2005, 5(3), 245-8).

Statins have anti-inflammatory and neuroprotective properties;lovastatin and atorvastatin protect animals against both acute andremitting-relapsing (RR) experimental autoimmune encephalomyelitis (EAE)disease via attenuation of the neuro-inflammatory CNS response and thepromotion of the Th2 differentiation of the naive myelin-specificT-cells. Treatment of CNS glial cells with the AMP activated proteinkinase (AMPK) activator,5-aminoimidazole-4-caboxamide-1-B-D-ribofuranoside (AICAR), protectedagainst lipopolysaccharide-induced pro-inflammatory response.Combination therapy with suboptimal doses of lovastatin and AICARadditively reversed or prevented EAE in animals by reducing diseaseseverity, CNS inflammation and neurodegeneration, compared with animalstreated with either drug alone at the same dose. (A. S. Paintlia et al.,Immunomodulatory Effect of Combination Therapy with Lovastatin and5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside AlleviatesNeurodegeneration in Experimental Autoimmune Encephalomyelitis, Am. J.Pathol., 2006, 169 (3), 1012-25).

Combination therapy with suboptimal doses of lovastatin and AICARcomplement each other by reversing pro-inflammatory responses in the CNSof EAE. Moreover the combination of the two agents reverses pathologicalchanges and cellular infiltration, promotes expression ofanti-inflammatory immune response, promotes induction of myelin-reactiveTh2 cells and alleviates neurodegeneration in the CNS of EAE animalmodels (Paintlia, Id.). Moreover, axonal and neuronal degeneration ininflammatory autoimmune CNS disorders can be prevented by a combinationof a neuroprotective agent, such as erythropoietin, and a steroid, suchas methylprednisolone, during the acute stage of the disease. (R. Diemet al., Combined Therapy with Methylprednisolone and Erythropoietin in aModel of Multiple Sclerosis, Brain, 2005, 128 (Pt 2), 375-85).

The premise of combining drugs in an MS application or RRMS applicationas described in this invention can be applied to other drugs which areused to treat MS either alone or in combination. This is especially trueconsidering that combination MS drugs are touted to work best whendifferent mechanisms of treating the disease are addressed. So, forexample, fingolimod, which has shown great promise for the treatment ofrelapsing multiple sclerosis, imparts its immunosuppressive effects bypreventing the egress of lymphocytes from lymph nodes. (L. Kappos etal., Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis, N. Engl.J. Med., 2006, 355 (11), 1124-40). Mitoxantrone also hasimmunosuppressive properties but its mechanism of immunosuppressiondiffers from that of fingolimod.

Methotrexate is an immuno-modulatory and an anti-inflammatory agent.Azathioprene immuno-modulates both T and B cells and is being consideredas an adjunct therapy in patients with RRMS who do not respond toglatiramer acetate or IFNβ. Intravenous immunoglobulin has been used totreat autoimmune neurological diseases but not MS. Perhaps theapplication of FMDD to a combination of immunoglobulin with another MSdrug can be used to treat MS or RRMS. Perhaps a combination of any twoor more drugs, most of which have different mechanisms of action anyway,can be combined to treat MS or RRMS. It is an embodiment of thisinvention that the combination drugs to treat MS or RRMS will bepotentiated when the combination is metal coordinated to produce an FMDDcomplex.

Other drugs that have been studied as combination therapies to treat MSinclude fumaric acid esters, daclizumab, matrix metalloproteinases,erythropoietin, cyclophosphoramide, valacyclovir, mycophenolate,tacrolimus, pentoxifylline, retinoic acid, fluoxetine, acetaminophen,ibuprofen, prednisone, inosine, selegeline, metacycline, pencillamine,tiazfurin, ribavirin and mizoribine. FMDD-designed complexes of theseagents are contemplated by this invention.

Schizophrenia

Rorick-Kehn, et. al. describe a mGlu 2/3 agonist, which is aconformationally locked fused ring glutamic acid derivative. (L. M.Rorick-Kehn et al., Pharmacological and Pharmacokinetic Properties of aStructurally Novel, Potent, and Selective Metabotropic Glutamate 2/3Receptor Agonist: In Vitro Characterization of Agonist(−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylicAcid (LY404039), J. Pharmacol. Exp. Ther., 2007, 321 (1), 308-17). Thecompound LY404039, may be beneficial for treatment of schizophrenia andanxiety. It works by selectively causing subtle alterations in neurontransmission resulting in the suppression of pathological glutamaterelease without affecting normal synaptic transmission. Thus it does notproduce unwanted side effects typically found with benzodiazepines andneuroleptics, such as sedation, abuse liability, dependence and motorside effects. Since this drug modulates excessive glutamate release,which is the cause for the side effects of other drugs, LY 404039 couldpotentiate the effects of other anti-psychotics by both ameliorating theglutamate release and lowering the dose through a neurotropic effect.Thus an FMDD-designed complex of an mGlu 2/3 agonist with otheranti-psychotics is anticipated by this invention.

Learning Disabilities and Autism Spectrum Disorders

Learning disabilities and Autism Spectrum Disorders are a heterogeneousgroup of diseases variably characterized by an impaired ability tolearn, speak, listen, read, write, spell, reason, organize information,and achieve appropriate social awareness. While recognizing the numerousdisparate etiologies and varied clinical presentations within pediatricand adolescent populations, the final common pathway of the diversecognitive dysfunction characterizing these disorders may be viewed asphysiological dysfunction of the ion channels, synapses and neuralnetworks which comprise the core of the maturing central nervous system.In particular, growing evidence suggests that recessive mutations inhighly conserved ion channel protein domains result in, in effect, ionchannelopathies with altered synaptic transmission and resultantneuropsychiatric dysfunction.

Specifically, mutations of both voltage-gated and ligand-gated ionchannels that regulate neuronal excitability and calcium-regulatedsignaling proteins have been associated with the development of autismand other related disorders. Additionally, it has been shown thatselective antagonism of NMDA receptors in mice impairs acquisition ofspatial learning behavior, while synchronous stimulation of both NMDAand AMPA receptors appear to be critical for normal excitatory synaptictransmission and plasticity throughout the developing brain and spinalcord. This suggests that a subtle, but synergistic, interplay existsbetween excitatory neuroreceptors, as well as an intrinsicsusceptibility to over-stimulation by asynchronous release of excitatoryamino acids, mainly glutamate and aspartate.

For example, Michael Chez and colleagues have recently demonstrated thatuse of memantine, a moderate-affinity antagonist of NMDA receptors, inpatients diagnosed with autism showed significant improvement inlanguage function, social behavior and self-stimulatory behaviors. Thesebenefits were hypothesized to be attributable to blockade of excessiveglutamate which leads to neuroglial inflammation and aberrant neuronalmigration, differentiation and development in the maturing brain. (M. G.Chez et al., Memantine as Adjunctive Therapy in Children Diagnosed WithAutistic Spectrum Disorders: An Observation of Initial Clinical Responseand Maintenance Tolerability, J. Child Neurol., 2007, 22 (5), 574-9).Thus, kinetic modulation of NMDA and AMPA receptors in a physiologicallysynergistic fashion could improve language development and socialbehavior in individuals with autism and other related disorders.

Chez has further found that use of carnosine in children with autism andother related disorders demonstrate improved neurobehavioral functiondue to its activating and neuroprotective affects on the frontal lobe.Via direct chelation of zinc and copper, carnosine may reduce zinc'sinhibitory affects on NMDA and GABA receptor-mediated synaptictransmission as well as the damaging influx of zinc and copper into thehippocampus and frontal lobes. This modulation of metal cations inhibitsthe epileptiform activity seen in one-third of autistic patients and mayimprove impairments in expression and behavior associated withautistic-related frontal lobe dysfunction. Trials combining theconcurrent use of memantine and carnosine in afflicted patients arecurrently ongoing and preliminarily show objective measurableimprovements in speech reception, socialization and behavior againsuggestive of synergistic potentiation of these individual therapeuticagents.

It is thus an embodiment of this invention that a FMDD complex for thetreatment of autism and other related disorders be comprised of an NMDAreceptor antagonist, magnesium as a potentiator of NMDA antagonism, andcarnosine. Preferred embodiments of this invention would therefore beremacemide-magnesium-carnosine, as well as remacemide-magnesium-curcumindue to curcumin's known anti-oxidant and anti-inflammatory propertieswithin the central nervous system. In the same respect, anotherpreferred embodiment of this invention would beremacemide-magnesium-glutathione due to glutathione's similar ability tosuppress oxidative injury.

Other FMDD complexes envisioned by this invention include thecombination of AMPA receptor agonists and antagonists along with achelating metal and NMDA receptor antagonists, carnosine, curcumin,glutathione and methylfolate. Also, the FMDD complex of metabotropicglutamate (mGlu5) receptor antagonists along with a chelating metal andNMDA receptor antagonists, carnosine, curcumin, glutathione andmethylolate are also contemplated. D-cycloserine, a partial agonist atthe glycine site of NMDA receptors with differing affinities for NMDAreceptor subtypes, has been positively associated with improvement insocial withdrawal symptoms in autistic children. (D. J. Posey et al., APilot Study of D-cycloserine in Subjects With Autistic Disorder, Am. J.Psychiatry, 2004, 161 (11), 2115-7). It is thus an additional embodimentof this invention that D-cycloserine is combined with carnosine,curcumin, glutathione or methylfolate along with a chelating metal in aFMDD complex.

Kinetic modulation of mGlu5-specific receptors, in addition to othermetabotropic glutamate receptors, is of special interest due to theobservations that mGlu5-specific receptor antagonism mimics clinicalNMDA receptor dysfunction (such as schizophrenia and addictivedisorders), possesses unique anxiolytic and anticonvulsant properties,and has been shown to successfully treat patients with Fragile X mentalretardation. Additionally, blockade of these G-protein coupled receptorsappear to attenuate NMDA receptor-mediated postsynaptic excitability inthe hippocampus, again suggestive of a kinetic interplay between thesereceptors that would be amenable to synergistic modulation byFMDD-designed metallo-pharmaceutical complexes.

Pentylenetetrazole (PTZ) has recently been shown to improve learning andmemory in patients with Down's Syndrome. Historically, PTZ has been usedas a circulatory and respiratory stimulant, and used experimentally as achemical kindling agent to induce and study seizure phenomenon inanimals due to its antagonistic GABA receptor properties. In Down'sSyndrome patients, it is hypothesized that PTZ's antagonism of GABA'sexaggerated inhibitory effects may improve neuronal and synaptictransmission and thus promote the acquisition, processing and retentionof novel information. (F. Fernandez et al., Pharmacotherapy forCognitive Impairment In a Mouse Model of Down Syndrome, Nat. Neurosci.,2007, 10 (4), 411-3).

It's been also observed that carnosine is protective against PTZ-kindledseizures in rats via the carnosine-histidine-histamine metabolicpathway. It is therefore an additional embodiment of this invention thata FMDD complexation of PTZ-magnesium-carnosine may promote theacquisition, processing and retention of information in Down's patientsand other patients with learning disabilities, while suppressing thedeleterious chemical kindling and seizure activity that may beprecipitated by PTZ usage. Additionally, synergistic potentiation ofthese pathways by combining PTZ with a NMDA receptor antagonist in aFMDD complex configuration due to its antiepileptic activity and itsattenuation of glutamate-induced excitotoxicity is also contemplated bythis invention.

Use in the Treatment of Cancer

Combination therapies are increasingly being used to treat various formsof cancer. For example, the recent advent of antiangiogenesis reagentsprovided a new and effective treatment option for various cancer types.It has been discovered, however, that tumor cells develop a resistantphenotype when subjected to the hypoxic conditions that antiangiogenesisreagents create. The resultant refractory condition can be treated withcombinations of antiangiogenesis and conventional cytotoxic agents suchas cisplatin, carboplatin, gemcitabine, fluorouracil or taxanes.Concomitant treatment may reduce the dosing requirement for theantiangiogenesis reagent, which may reduce the potential for cellmutation and allow the needed vascularization for delivery of thecytotoxic reagent. Thus, fluorouracil and leukovorin have been used ascombination therapy to treat colorectal cancer.

Although unrelated mechanistically, other specific examples ofcombination cancer therapies include the CHOP and MOPP protocols fornon-Hodgkins and Hodgkins lymphomas, BEP for testicular carcinoma andantiandrogens combined with GnRH agonist such as goserelin orleuprolide.

Prostate Cancer

Whereas each of these anticancer cocktails are more potent ascombinations, the synergy between them is limited mechanistically. Thereare anticancer agents that when combined in a single therapeutic regimenare very effective but their efficacy could be further improved if thesynergy between the reagents could be kinetically controlled, that isthe different agents in the cocktail were to reach their target receptoror cofactor with well coordinated timing. Antiandrogen therapy combinedwith histone deacetylase inhibitors is an example where the two reagentswhen combined in a kinetically controlled synergistic manner wouldexhibit enhanced effectiveness in treating prostate cancer.

Antiandrogen therapies remain a very viable approach to treatingprostate cancer, notwithstanding some of the adverse effects seen withtheir use. Many patients undergoing this treatment regimen may determinethat the treatment's benefits outweigh the adverse effects and justifyits discomfort and risk.

One of the major problems that exist with many anticancer therapies,particularly antiandrogen therapy, is that patients often becomeresistant to the drug. The risk of becoming refractory may not halttreatment, but refractory prostate cancer is a very difficult disease tomanage. Secondary hormone therapy, chemotherapy and bisphosphonatetherapy have been recommended as a second line of treatment for a selectpopulation of patients who no longer respond sufficiently toantiandrogen therapy. (M. Diaz & S. G. Patterson, Management ofAndrogen-independent Prostate Cancer, Cancer Control, 2004, 11 (6),364-73). These options may not be the best ones available and a methodof prolonging the efficacy of antiandrogens, particularly bicalutamide,may prove to be the best-in-class approach to refractory prostatecancer.

The postulated mechanisms to explain why patients undergoingantiandrogen therapy become refractory include 1) androgen receptorgenes mutate causing the antiandrogen to behave as an agonist; 2)oncogene mediated MAP kinase signaling increases causingligand-independent activation of the androgen receptor and 3) growth andsurvival functions of the androgen receptor are bypassed rendering theandrogen receptor no longer relevant to disease progression.

Ligand-independent activation of the androgen receptor is believed to bedue to its over expression. Androgen receptor must bind its ligand toconfer hormone-refractory growth, and a modest increase in receptorconcentration permits the receptor to function despite lower levels ofandrogens, such as in castrated patients or patients taking GnRH. Thisis likely due to alterations in the balance between coactivators andcorepressors that can affect androgen receptor activation. (C. D. Chenet al., Molecular Determinants of Resistance to Antiandrogen Therapy,Nat. Med., 2004, 10 (1), 33-9).

This disruption of the balance of gene expression regulators also playsa role in the refractory mechanism in those cases when the antagonistbehaves like an agonist. The mechanism of hormone-refraction being dueto antagonist-to-agonist switch was supported by hormone-refractorytumors having more androgen receptor protein than their parentalhormone-sensitive counterparts. Furthermore, it was found that thisantagonist-to-agonist conversion was not unique to bicalutamide orparticular hormone-refractory cell lines (Chen, Id.). Thus, themechanism of hormone refractory antiandrogen therapy is somewhatubiquitous amongst cancer cell lines and is not relegated to a singlereceptor class.

Long term and continued exposure of androgen receptor containing cellsto bicalutamide treatment causes an increase in the amount of androgenreceptors that are expressed. An increase in the number of androgenreceptors will increase the variation in their expression and shift therelative abundance of coactivators and corepressors assembled on thepromoters of androgen receptor genes. This leads to the decreasedability to recruit the necessary coactivators necessary fortranscription of gene products that shut down production of cancercausing genes.

Whereas RNA polymerase or histone acetylation was not recruited topromoters in response to bicalutamide in cells with normal amount ofandrogen receptors, polymerase II was present in cells with excessandrogen receptor treated with bicalutamide (Chen, Id.). This impliesthat histone acetylation may also play a role in the shifting of therelative abundance of coactivator and corepressors. Since chronicexposure of androgen receptors to bicalutamide initiates a cascade ofevents leading to a disruption of the mode of action of those receptors,keeping bicalutamide dose low or potentiating its effect with anotheranticancer drug may prevent increased androgen receptor expression.

Histones are protein structures that make up chromatin, which wrapsaround the DNA molecule. They are that part of the nucleosome that isdirectly involved in the regulation of gene product expression. When thelysine residues on histones are charged, the chromatin tightens up onthe DNA strand, thereby preventing expression of the gene products onthe DNA. Neutralization of the histone charge, primarily by acetylationof the lysine residues, loosens the chromatin from the DNA, allowing forthe DNA to transfer its message to RNA and ultimately allowing geneexpression.

The facilitation of gene expression by the acetylation of histone iscatalyzed by histone acetyltransferase (HAT). Conversely, the shut downof gene expression through a reverse acetylation process ordeacetylation, as it is referred, is catalyzed by histone deacetylase(HDAC). HDACs restore the positive charge on lysine residues by removingacetyl groups and thus are involved primarily in the repression of genetranscription by compacting chromatin structure. (M. R. Acharya et al.,Rational Development of Histone Deacetylase Inhibitors as AnticancerAgents: A Review, Mol. Pharmacol., 2005, 68 (4), 917-32).

The discovery of the acetylation of histone to regulate gene expressionhas opened up many areas of research including the application of thisbiochemical machinery to gene regulated antineoplastic agents. Themajority of work in this area has focused on inhibiting HDAC.

The general effect of HDAC inhibitors (HDACi) often seen in cell linesis cytotoxicity, differentiation, inhibition of proliferation andinduction of apoptosis. (A. J. de Ruijter et al., Histone Deacetylases(HDACs): Characterization of the Classical HDAC Family, Biochem. J.,2003, 370 (Pt 3), 737-49). Treatment of tumor cells with HDAC inhibitorstriggers both the intrinsic pathway and sensitizes tumor cells to thedeath ligands that initiate the extrinsic pathway of apoptosis. (K.Bhalla & A. List, Histone Deacetylase Inhibitors in MyelodysplasticSyndrome, Best Pract. Res. Clin. Haematol., 2004, 17 (4), 595-611).Cancer can result from inappropriate silencing of critical genes leadingto inactivation of tumor suppressor gene (TSG). The reactivation of TSGby allowing the expression of the critical genes through inhibition ofHDAC has enormous potential for preventing and treating cancer (Acharya,Id.).

For example, when six cancer cell lines were pretreated with HDACinhibitors followed by treatment with a variety of cancer drugs thattarget chromatin DNA, there was a more than ten-fold sensitization ofcells. The data suggested that loosening up the chromatin structure byhistone acetylation can increase efficiency of several anticanceragents. A very widely studied HDACi, suberoylanilide hydroxamic acid(SAHA), significantly potentiated the DNA damage by topoisomerase IIinhibitors; however the synergy was dependant on the sequence of drugadministration and expression of target (Acharya, Id.).

As alluded to earlier, androgen receptor actions seems to be mediatedexclusively through genotropic mechanisms, thus one can also envisiondrugs that present androgen receptor nuclear translocation or impairassembly of androgen receptor transcription complexes on target genes(Chen, Id.). The effect of HDACi on gene expression is believed not tobe a general one, but rather involves alteration of the transcription ofa specific subset of genes (de Ruijter, p. 746).

HDAC responsive genes belong to the cell cycle, apoptosis, andtranscription factor classes. De Ruijter identified a myriad of otherresponsive genes including genes for matrix metalloproteinase-2,interleukin-6 receptor, interleukin-2, -8 and -10, intercellularcell-adhesion molecule-1, carboxypeptidase A3, human telomerase reversetranscriptase and vascular endothelial growth factor. De Ruitjer did notexpressly identify androgen-sensitive genes but since it is known thatHDACi prevents androgen antagonist resistance, the two anti-canceragents are intrinsically linked (de Ruijter, Id.). It is possible thatthe coactivators involved in transcription due to antiandrogen receptorligation are promoters of HDAC. This premise is supported by the factthat when the HDAC inhibitor, 7-phenyl-2,4,6-hepta-trienoyl hydroxamicacid, was combined with bicalutamide, an additive effect on growthinhibition and apoptosis in androgen resistant prostate cancer cells wasfound. It was also shown that this HDACi worked synergistically withbicalutamide on growth inhibition of cancer cells.

It appears that bicalutamide's ability to block the androgen receptorfrom suppression of anticancer gene product transcription (i.e.recruiting required coactivators for transcription) can be potentiatedby the synergistic introduction of an HDACi, another agent that promotestranscription. In other words, the genetic events that are connectedwith blocking the androgen receptor are intrinsically linked to themechanisms associated with activation of gene transcription.Furthermore, inhibition of HDAC may suppress the events responsible forthe shifting in the coactivator and corepressor recruitment linked toantiandrogen resistance.

Potentiating the effects of an antiandrogen through promotion oftranscription by HDAC inhibition of intrinsically linked gene productsis best accomplished if the effects of the two reagents were kineticallylinked. Thus, the key element in the optimum synergistic combination ofantiandrogens and HDAC inhibitors is that that the two anticancer agentsare introduced to the cancer cells simultaneously. This is bestaccomplished if the antiandrogen and the HDACi are presented to the cellas a single molecular entity.

Delivering an antiandrogen drug and an HDACi to the cell as a singlemolecular entity can be accomplished by covalently attaching a linker toeach of the anticancer reagents. It would be unlikely, however, for theHDACi to migrate to the nucleus when it is attached to the antiandrogenthat is bound to the receptor. Therefore a cancer therapy that wouldallow the combination therapies to work in concert yet not affect theefficacy of the individual components would have a distinct advantageover a drug where the two reagents were combined in a more permanentcovalent bond.

Bicalutamide and hydroxamic acid can form stable metal coordinatedcomplexes. A metal complexed with a hydroxamic acid derived HDACi andbicalutamide, or its chemical and pharmacologic equivalent, would havesufficient stability to reach the cancer cell as an intacthetero-ligated complex but would breakdown and release the metal andHDACi upon interaction with the androgen receptor. The HDACi would thentransfect the cell membrane and migrate to the nucleus as usual andpromote transcription of gene products that potentiate the effect of theandrogen antagonist. Thus it is an embodiment of this invention that anantiandrogen drug and an HDACi drug complexed with a metal are deliveredto the androgen receptor, thereby releasing the HDACi to the nucleus ina kinetically controlled manner to impart optimum synergy between thereagents and thereby prevent the onset of a refractory condition.

Both bicalutamide and hydroxamic acid have been shown to chelate metals.Since some hydroxamic acids are siderophores the ideal metal may beiron. Therefore, it is an embodiment of the invention that thebiologically synergistic anticancer reagent consist of an antiandrogen,such as bicalutamide, and a hydroxamic acid class of HDAC inhibitor,such as SAHA, and a metal that will form a stable complex with bothanticancer ligands. It is a preferred embodiment of the invention thatthe metal be iron.

The application of metal coordination to optimize synergistic effectsbetween two or more anticancer reagents is not limited to antiandrogens.In one study, it was proposed that HDACi might activate components ofthe death receptor pathways in various solid tumors. Furthermore, it wasshown that in several cases apoptosis of tumor cell lines was inducedthrough synergistic action of HDACi with exogenously added tumornecrosis factor-related apoptosis inducing ligand (TRAIL). (S. Minucci &P. G. Pelicci, Histone Deacetylase Inhibitors and the Promise ofEpigenetic (and more) Treatments for Cancer, Nat. Rev. Cancer, 2006, 6(1), 38-51).

Another report proposed that since HDAC inhibitors induce cell cyclearrest through the induction of certain tumor suppression genes (e.g.,p21^(WAF1/CIP1)), that colon cancer and lung cancer cells would besensitized to TRAIL-induced lethality. It was discovered, however, thatwhen cells were simultaneously exposed to HDAC inhibitors with TRAIL, asopposed to sequential exposure, a large increase in apoptosis wasobtained. This study also suggested the importance of incorporating akinetic component to synergistic application of anticancer agents. Theresearchers believed that co-administration of TRAIL with HDACinhibitors indicated simultaneous activation of the extrinsic andintrinsic pathways leading to a dramatic increase in mitochondrialinjury and activation of caspase cascades. This was supported by earlierstudies that showed that TRAIL enhances the antitumor activity ofmultiple convention cytotoxic drugs, which primarily act through theintrinsic/mitochondrial pathway, including etoposide, cytosinearabinoside, cisplatin, doxorubicin and paclitaxel. (R. R. Rosato etal., Simultaneous Activation of the Intrinsic and Extrinsic Pathways byHistone Deacetylase (HDAC) Inhibitors and Tumor Necrosis Factor-relatedApoptosis-inducing Ligand (TRAIL) Synergistically Induces MitochondrialDamage and Apoptosis in Human Leukemia Cells, Mol. Cancer. Ther., 2003,2 (12), 1273-84).

Moreover, the antisense molecule, custirsen has shown potential incombination with either docetaxel or mitoxantrone to treat hormonerefractory prostate cancer. Thus the combination of a TRAIL with an HDACinhibitor and a metal that will form a stable complex with bothanticancer ligands is an embodiment of the invention.

Leukemia

It is a further embodiment of this invention that treatment for acutepromyelotic leukemia (APL) can be realized through FMDD complexapplication of retinoic acid (RA) and an HDACi. Promyelotic leukemiazinc finger (PLZF) does not respond to RA treatment because the RA willnot turn on the conformational switch that leads to the release ofHDAC-containing complexes, which ultimately lead to powerful bursts ofdifferentiation; this is counter to hyperproliferation associated withcancer malignancies. However, the combination of RA with HDACi isextremely effective in reactivating RA target genes and triggers acellular response in vitro and in vivo in PLZF-RAR-positive APLpatients. In fact, the HDACi, phenylbutryate, was used in combinationwith RA to treat a 13 year old girl with relapsed APL.

In a further embodiment of this invention, HDAC inhibitors can besynergistically combined with antimetabolites through metal coordinationto potentiate the antileukemic effect of each of the components of themetal coordination complex.

Antimetabolites interfere with DNA production and thus cell division andthe growth of tumors. Antimetabolites, which are analogs of nucleosides,disrupt incorporation of the natural building blocks of DNA, either bydirect competition or by inhibition of DNA production through inhibitionof dihydrofolate reductase. Many of these antimetabolites belong to aclass of compound called purines. The purine analogs includeazathioprene, mercaptopurine, thioguanine, fludarabine,arabinofuranosylcytosine (ara-C), gemcitabine, pentostatin andcladribine.

It has been shown that incorporation of fludarabine into leukemic cellDNA appears to be required for lethality. Furthermore, HDACi markedlyincreases fludarabine induced mitochondrial injury and apoptosis in asequence-dependant manner, resulting in highly synergistic antileukemicinteractions. Moreover, the enhanced lethality of the drug combinationis associated with perturbations in several signal transduction pathwayssuch as ERK inactivation, JNK activation, expression of apoptoticproteins and increases in ROS. (S. C. Maggio et al., The HistoneDeacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabineto Induce Apoptosis in Human Leukemia Cells, Cancer Res., 2004, 64 (7),2590-600).

Prior exposure of leukemic cells to HDACi maximizes fludarabinelethality, indicating that HDAC inhibitors trigger time-dependant eventsthat increase the apoptotic potency of fludarabine. Other studies haveshown that ROS increase, mitochondrial dysfunction, caspase activationand loss of clonogenic survival all contribute to this synergisticpotentiation.

Thus it is an embodiment of this invention that purine analogs that actas DNA antimetabolites when combined with an HDAC inhibitor in asynergistic manner will potentiate each other in promoting cell death inleukemic cells. It is a further embodiment of this invention that thesynergy between the purine analog and the HDACi is optimized by precisekinetic control imparted through metal coordination of both the purineanalog and the HDACi. In a preferred embodiment of the invention, thepurine analog and the HDACi will form stable metal complexes.Mercaptopurine can form stable metal complexes, therefore in a preferredembodiment of the invention the purine analog is mercaptopurine.Likewise, SAHA can form stable metal complexes, therefore in anotherpreferred embodiment of the invention the HDACi is SAHA. In a mostpreferred embodiment of the invention the antileukemia drug is amercaptopurine:metal:SAHA coordination complex.

Lung Cancer

Alimta is an antimetholite with a molecular structure similar to folicacid. Its indications are for the treatment of pleural mesothelioma andnon-small lung cell cancer. Folic acid and vitamin B-12 help manageAlitma's toxicity. (C&E News, Apr. 16, 2007, p. 45). Thus, a combinationof alimta and folic acid synergistically delivered as described hereinwill potentiate the effects of alimta by reducing its toxicity.Therefore, Alimta-metal-folic acid and Alimta-metal-vitamin B-12 areembodiments of this invention.

Use in the Treatment of Cardiovascular Disorders

The importance of combination therapy to control blood pressure is wellknown and it has been estimated that 70% of patients with cardiovascularconditions will require combination therapy. (J. L. Pool, Direct ReninInhibition: Focus on Aliskiren, J. Manag. Care Pharm., 2007, 13 (8 SupplB), 21-33). Aliskiren, which is a direct renal inhibitor (DRI), isgaining importance in treating hypertension but has some adverseeffects. These adverse effects may be avoided when used in combinationwith other cardiovascular drugs. Since renin is an upstream regulator ofBP and angiotensin converting enzyme inhibitor (ACEI) and angiotensin IIreceptor antagonist (ARB) downstream, it makes sense that they wouldpotentiate each other. Thus it is an embodiment of this invention thataliskiren be combined with an ACEI or an ARB in a metal complex havingbeneficial effects in treating hypertension and other related diseasestates. Most recently, the positive benefits of combining aliskiren andthe ARB, losartan, to treat type 2 diabetic patients with diabeticnephropathy and hypertension due to the synergistic effects of dualblockade of the renin-angiotensin-aldosterone system (RAAS) has beenreported. (S. Anderson & R. Komers, Aliskiren Combined With losartan inDiabetes and Nephropathy, N. Engl. J. Med., 2008, 359 (10), 1069; authorreply 1069-70).

Combining agents that increase plasma renin activity (PRA) with agentsthat neutralize this activity appears to be a rational approach totreating hypertension. This duo effect from PRA highlights theimportance of diuretics in balancing this effect. Moreover, combinationtherapy reduces the incidence of hypokalemia. (Tekturna,http://www.medscape.com/infosite/tekturna/article-pharmocology). Thus itis an embodiment of this invention that aliskiren be combined with adiuretic in a metal complex and that the new metal coordination complexhave optimum potentiated effects in treating hypertension and otherrelated disease states. It stands to reason that diuretics can also becombined in a metal coordination complex with ARB's and ACEI's topotentiate the antihypertensive effects of those biologically activeagents and thus ACEI-Mg-furosemide, ARB-Mg-furosemide andaliskiren-Mg-furosemide are preferred embodiments of this invention.

Ranolazine is a novel partial inhibitor of fatty acid oxidation andselective inhibitor of late sodium channels in myocardial cells whichappears to ameliorate symptoms of angina due to myocardial ischemiawithout adversely altering cardiac hemodynamics. Ranolazine shiftsadenosine-5′-triphosphate production from ischemia-induced fatty acidproduction to more oxygen-efficient carbohydrate oxidation and decreasesassociated myocardial sodium influx thereby reducing cellular calciumoverload, which decreases left ventricular wall tension and furtherreduces myocardial oxygen demand.

Ranolazine is indicated for treatment of chronic stable angina inindividuals with angina refractory to more standard anti-anginalmedications. It has been shown to decrease angina episodes inindividuals with coronary artery disease on maximal doses of amlodipine.In addition, it has been shown to both decrease angina episodes andincrease exercise tolerance in individuals taking concomitant atenolol,amlodipine or diltiazem without significantly altering either the heartrate or blood pressure. Ranolazine, along with other late sodium-channelblockers, may also be used in the treatment of congestive heart failure,myocardial infarctions, cardiac arrhythmias, diastolic dysfunction andintermittent claudication.

It is an embodiment of this invention that FMDD complex formulations ofranolazine combined with calcium-channel blockers such amlodipine,diltiazem and verapamil will synergistically reduce the influx ofdamaging calcium into ischemic myocardium in the medical settings listedabove while improving cardiac contractility, increasing coronary bloodflow and reducing myocardial oxygen demand. A preferred embodiment ofthis invention is Ranolazine-Mg-Diltiazem. Other embodiments of thisinvention which would synergistically exploit the known anti-ischemicproperties of beta-blockers and nitrates would beRanolazine-Mg-metoprolol and Ranolazine-Mg-isosorbide mononitrate.Additionally, Ranolazine-Mg-furosemide would be beneficial in patientswith congestive heart failure due to decreased left ventricular functionsecondary to myocardial ischemia.

Use in the Treatment of Gastrointestinal Disorders

Crohn's disease (CD) and ulcerative colitis (UC) are chronicinflammatory diseases of the gastrointestinal tract encompassed by theterm, inflammatory bowel diseases (IBD). Aminosalicylates such asmesalamine (5-aminosalicylic acid) have historically been a mainstay inthe treatment of UC and CD, having multiple anti-inflammatory effectsincluding inhibition of cyclooxygenase, lipoxygenase, B-cells andinflammatory cytokines. (R: B. Sartor, Mechanisms of Disease:Pathogenesis of Crohn's Disease and Ulcerative Colitis, Nat. Clin.Pract. Gastroenterol. Hepatol., 2006, 3 (7), 390-407). Additionally,mesalamine and its formulations have been shown to activate specificperoxisome proliferator-activator receptor ligand (PPAR), nuclearreceptors that regulate cellular differentiation and induce apoptosis.(W. J. Sandborn, Oral 5-ASA Therapy in Ulcerative Colitis: What Are theImplications of the New Formulations?, J. Clin. Gastroenterol., 2008, 42(4), 338-44).

Administration of systemic and non-systemic steroids in IBD result in abroad spectrum of ameliorating immunological effects includinginhibition of migration of neutrophils to inflammatory sites,suppression of the recruitment and proliferation of lymphocytes,monocytes and macrophages, and reduced production of inflammatorymediators such as cytokines, leukotrienes and prostaglandins (Sandborn,Id.). In turn, immunomodulators such as 6-mercaptopurine (6-MP) and itsprodrug azathioprine (AZA) interfere with nucleic acid synthesis, thusinhibiting the proliferation of activated lymphocytes and inducingapoptosis in patients with refractory or steroid-resistant disease.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid, alsointerferes with purine metabolism by inhibiting synthesis of guanosinenucleotides such as GTP and thereby reducing the proliferation ofT-cells. Secondary effects of MMF may be to induce tolerance ofdendritic cells to antigenic stimuli, thus rendering T-cells lessresponsive and inhibition of adhesion molecule expression on lymphocytesvia reduced glycosylation. MMF's mechanism of action is similar toazathioprine and is also considered for use in steroid-resistant andrefractory IBD patients.

While the aminosalicylates remain the first-line therapy for theinduction and maintenance of mild to moderate UC, their efficacy in thetreatment of CD is less supported by the literature. Additionally, aproportion of IBD patients are refractory to aminosalicylates requiringchronic administration of various steroid preparations, especially inpatients with CD. These steroid-dependent subgroups of patientstypically require concurrent use of AZA and 6-MP as a steroid-sparingstrategy, although these immunosuppressant agents may be associated withmultiple adverse effects, especially in patients who lack thiopurinemethyl transferase (TPMT), an enzyme which metabolizes azathioprine andrendering them at increased risk of bone marrow suppression and othertoxicities

Combinatorial therapies for IBD have the theoretical advantage ofsynergistic immunosuppression of cellular and humoral inflammation,reduction of drug toxicity in steroid-dependent or steroid-refractorypatients, and improved patient compliance, which may reduce the risk ofneoplastic transformation in chronic UC patients. For example, the FMDDcomplex combination of tixocortol, a high potency topical corticosteroidwith good metabolic stability in the bowel, with mesalamine would havetheoretical therapeutic benefits for both the induction and maintenanceof UC and CD. This benefit may manifest by enhancing delivery of theactive moieties to the targeted inflammation by reducing systemicabsorption while reducing overall dosing requirements. This“steroid-sparing” effect of this FMDD entity would also result inimproved patient compliance and reduced long-term toxicities. An FMDDcomplex combination of tixocortol and AZA/6-MP would demonstrate thesame therapeutic benefits in early or steroid-dependent IBD patients.

The FMDD complex combination of MMF with AZA/6-MP may be useful insteroid-refractory IBD patients or to maintain remission in severe andprogressive disease where surgical intervention is being contemplated asa last resort. Both drugs have a similar and possibly synergisticmechanism of action by interfering with purine synthesis and suppressingrapidly proliferating T-cell and B-cell lineages. Both drugs haveindependently demonstrated benefit in IBD who fail to show improvementto administration of systemic and parental corticosteroids in fulminantcases. Alternatively, FMDD complex combinations of MMF with tixocortoland mesalamine may be beneficial in IBD patients who have shown toxicityor resistance to AZA/6-MP administration or have reduced or absent TPMTenzyme activity.

Metal chelation of FMDD complexes containing mesalamine may enhance thedistal delivery of the active drug moieties, such as typically seen withthe bacterial azoreductase cleavage of IBD patients treated withsulfasalazine, by mimicking the azo-bond which prevents the prematureintestinal absorption and hepatic metabolism of mesalamine. This effect,in turn, would further reduce the incidence of toxicity and poor patientcompliance caused by the unintended systemic absorption of mesalamine.

Use in the Treatment of Diabetes

It has been shown that insulin's action in facilitating the metabolismof glucose is potentiated by the co-administration of certain glycancontaining insulin mediators. Of particular note is the glycemic controlimparted by the aminosugar-inositol disaccharides. It is especiallynoteworthy that D-chiroinositol (DCI), either as part of a disaccharideor alone has glycemic modulation effects in vivo. (J. Larner et al.,Isolation, Structure, Synthesis, and Bioactivity of a Novel PutativeInsulin Mediator, A Galactosamine Chiro-inositol Pseudo-disaccharideMn2+ Chelate With Insulin-like Activity, J. Med. Chem., 2003, 46 (15),3283-91). Therefore, the insulin-metal-inositol coordination complex isan embodiment of this invention. Since insulin is commercially availableas a zinc complex, it is a preferred embodiment of this invention thatthe diabetes therapeutic agent is insulin-zinc-inositol. In an even morepreferred embodiment of the invention, the complex is insulin-zinc-DCI.In a most preferred embodiment of the invention the complex isinsulin-zinc-2-deoxy-2-amino-galactopyranosyl-DCI.

Diabetes provides a unique application for FMDD because if the metalvanadium were used, an additional therapeutic effect could be impartedbeyond what the two biologically active ligands (e.g. inositol andinsulin) provide. Thus, it is an additional embodiment of this inventionthat the metal is vanadium.

Other FMDD Ligands

The number and types of FMDD ligands and FMDD complexes and diseases andmedical conditions treated by FMDD complexes are not intended to belimited by the disclosure herein. Other complexes and medical conditionsmay be recognized by those of skill in the art upon contemplation of thepresent disclosure.

For example there are biologically active agents with known benefits forvarious neurodegenerative/neurological conditions. In addition to thealready mentioned methylfolate and carnosine, 1) gamma-3-fatty acids,which have been used to treat schizophrenia and ADHD, 2) cannabinoids,which have been used in the treatment of pain, coeliac disease,Alzheimer's disease, multiple sclerosis and epilepsy, 3) flupirtine, anNMDAR antagonist, which has been used in the treatment of pain,Parkinson's disease and fibromyalgia, 4) glutathione, a tripeptide whichplays a major role as an anti-oxidant and co-factor in numerous cellularmetabolisms, and has been used in the treatment of PD, Autism, and maleinfertility, 5) curcumin, a beta-diketone which has been used to treatgliomas and other cancers, and is also an inhibitor of hepaticP-glycoprotein which may result in beneficial chemosensitization, and 6)N-acetylcysteine, which has been used to treat Autism, are all viableFMDD candidates that can potentiate the effects of otherpharmaceutically active agents. (Yoshikawa et al., Inflamatory BowelDisease Preventative and Curative Agent Containing Zinc L-carnosine Saltas Active Ingredient, 1991, 1993; T. Yoneta et al., Wound HealingAccelerators, 1997; Atkins, Specialty Pharma., May 2005, 1 (1), p. 31).

Moreover, (−)-Epigallocatechin-3-gallate alters cleavage of amyloidprecursor protein decreasing production of amyloid plaques, thus makingthat agent an FMDD ligand candidate for the treatment of Alzheimer'sdisease. (J. Tan, Neurosci., 2005, 25, 8807).

It is an embodiment of this invention that the combination of FMDDligands, metal, and other ingredients or components impartsthermodynamic stability to the entire metal coordination complex. It isan embodiment of this invention, that FMDD ligands that are designed toprovide thermodynamic stability to the metal coordination complex, suchas salicylaldehyde, dipyridyl or ethylenediamine, are incorporated intothe drug:metal complexes to impart beneficial physicochemicalproperties. It is a further embodiment of this invention that thebenefit of the FMDD ligand is to stabilize the drug:metal complex incertain environments, such as in biological systems.

In a preferred embodiment of the invention the disease state whosetreatment is potentiated by this invention includes pain, cancer,Parkinson's disease, epilepsy, ADHD, Alzheimer's disease, hypertension,schizophrenia, multiple sclerosis, migraine headaches and coeliacdisease. In a more preferred embodiment of the invention the diseasestate whose treatment is potentiated by this invention is Parkinson'sdisease. In a most preferred embodiment of this invention the diseasestate whose treatment is potentiated by this invention is painmanagement.

According to the present disclosure, one embodiment may include acoordination complex including a first biologically active moiety, asecond biologically active moiety, and a metal, wherein the firstbiologically active moiety and second biologically active moiety arebound to the metal by covalent coordination bonds, and wherein the firstbiologically active moiety and second biologically active moiety aredifferent. In certain embodiments, the first biologically active moietyand the second biologically active moiety are capable of potentiatingeach other.

Certain embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of opioids, NMDA receptorantagonists, voltage-gated ion channel blockers, NSAIDs, acetylcholinereceptor agonists, adenosine neurotransmitters, P2 receptor antagonists,cannabinoids, vanilloids, VR1 receptor agonists, substance P, NKreceptor antagonists, CGRP1-receptor antagonists and nitric oxide.

Certain other embodiments may include a coordination complex, whereinthe first biologically active moiety and the second biologically activemoiety are selected from the group consisting of triptans, NSAIDs, andopioids, modulators of voltage-gated sodium and calcium channels, GABAreceptors and the AMPA/kainate subtype glutamate receptors, GABA uptakeinhibitors, voltage-dependant sodium channels blockers,glutamate-mediated exicitatory neurotransmission reducers, excess nitricoxide production inhibitors, hydroxyl radical scavengers, carbonicanhydrase inhibitors, antioxidants, norepinephrine release inhibitors,5-HT2 receptor modulators, adenosine neurotransmitters, vanilloids andthe VR1 receptor agonists, Substance P, CGRP1-receptor and NK receptorantagonists.

Further embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of ionotropic glutamatereceptor antagonists and agonists, metabotropic glutamate receptorantagonists, MAO-B inhibitors, dopamine receptor agonists, and NMDAreceptor antagonists.

Still further embodiments may include a coordination complex, whereinthe first biologically active moiety and the second biologically activemoiety are selected from the group consisting of NMDA receptorantagonists, HDAC inhibitors, cannabinoids, folic acid derivatives andcarnosine-related compounds. As used herein, “carnosine-relatedcompounds” include carnosine, anserine, and homocarnosine.

Certain embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of NMDA receptorantagonists, polyamine site antagonists, glycine-β receptor antagonists,carnosine-related compounds, and cannabinoids.

Other embodiments may include a coordination complex, wherein the firstbiologically active moiety and the second biologically active moiety areselected from the group consisting of statins, immunosuppressants,steroids, AMPK activators, anti-inflammatory reagents and cannabinoids.

Still other embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of anti-psychotics,gamma-3-fatty acids, and glutamic acid analogs.

Further embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of AMPA receptor agonists,AMPA receptor antagonists, NMDA receptor antagonists, carnosine-relatedcompounds, gamma-3-fatty acids, G-protein receptor antagonists,antioxidants, anti-inflammatory reagents, glycine-site NMDA agonists,GABA receptor agonists and metabotropic glutamate receptor antagonists.

Further still, certain embodiments may include a coordination complex,wherein the first biologically active moiety and the second biologicallyactive moiety are selected from the group consisting of antiangiogenesisagents, cytotoxic agents, antiandrogens, GnRH agonist, HDAC inhibitors,topoisomerase II inhibitors, antimetabolites, tumor necrosisfactor-related apoptosis ligands (TRAIL), retinoic acid derivatives andvitamins.

Certain embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of direct renalinhibitors, angiotensin converting enzyme inhibitors, angiotensin IIreceptor antagonists, late sodium-channel blockers, calcium-channelblockers, and partial inhibitors of fatty acid oxidation.

Other embodiments may include a coordination complex, wherein the firstbiologically active moiety and the second biologically active moiety areselected from the group consisting of aminosalicylates, steroids,immunomodulators, cannabinoids, PPAR ligand activators,anti-inflammatory reagents and P-glycoprotein inhibitor.

Still other embodiments may include a coordination complex, wherein thefirst biologically active moiety and the second biologically activemoiety are selected from the group consisting of glycan containinginsulin mediators, sulfonylureas, biguanides, thiazolidinediones, PPARligand activators and inositols.

Certain embodiments according to the present disclosure include a methodof treating a condition, including administering to a patient in needthereof a coordination complex comprising a first biologically activemoiety, a second biologically active moiety, and a metal, wherein thefirst biologically active moiety and the second biologically activemoiety are bound to the metal by covalent coordination bonds, andwherein the first biologically active moiety and the second biologicallyactive moiety are different. In some embodiments, the condition mayinclude pain, migraines, Parkinson's disease, Alzheimer's disease,multiple sclerosis, schizophrenia, attention deficit hyperactivedisorder, autism spectrum disorders, cancer, hypertension, digestivediseases, diabetes, epilepsy, and combinations of any thereof.

In certain embodiments, the ligands may bind to the metal, and form aring structure. In other embodiments, the ring structure is selectedfrom the group consisting of a four member ring, a five member ring, asix member ring, a seven member ring, and an eight member ring. Infurther embodiments, the ring structure is selected from the groupconsisting of a five member ring and a six member ring.

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Treatment ofanimals, especially a human, with an effective dosage of an embodimentof the present disclosure would involve the administration of thecompound or composition in an appropriate form to the animal. Theembodiments of the present disclosure can be administered in a varietyof ways including but not limited to oral, parenteral, nasal, buccal,rectal, vaginal, ocular, pulmonary or topical. Alternatively,administration may be by intratracheal instillation, bronchialinstillation, intradermal, subcutaneous, intramuscular, intraperitonealor intravenous injection. Dosage forms include tablets, troches,dispersions, suspensions, solutions, capsules, creams, ointments,aerosols, and the like. They may be conveniently presented in unitdosage form and prepared by any of the methods well-known in the art ofpharmacy.

The following examples are intended to illustrate, but not to limit, thescope of the invention. It is to be understood that other proceduresknown to those skilled in the art may alternatively be used.

EXAMPLES

Based on the methodology currently employed by the present inventors toprepare metal coordinated and hetero-ligated pharmaceuticals, thechemistry adapts well to parallel synthesis and purificationinstrumentation. The Syncore Polyvap/Reactor (Buchi Syncore Reactor R24,includes the vacuum/inert gas cover, reflux module, and the standardrack R24, BÜCHI Labortechnik AG, Switzerland) gives high efficiency andmaximum flexibility for parallel and combinatorial synthesis. Work-upand purification is achieved utilizing Oasis HLB (hydrophilic-lipophilicreversed-phase solid-phase extraction) cartridges (Waters Corporation,Milford, Mass.) employing a vacuum extraction manifold capable ofprocessing multiple samples. Two cases: 1) Dopa HLP's are currentlyprepared by adding DOPA, an amino acid, and solvent, followed by Ba(OH)₂to a flask under an inert atmosphere with stirring. Metal sulfate isthen added and the reaction is heated, filtered to remove BaSO₄, andloaded onto a solid phase extraction cartridge. The unreacted aminoacids elute in the aqueous fraction, the (dopa)metallo(amino acid) in20% MeOH, and any remaining BaSO₄ is retained. 2) (salicylato)zinc(aminoacid) is currently prepared by reacting Zn(sal)₂ with an amino acid inH₂O with heat. The reaction is filtered and loaded on to a solid phaseextraction cartridge and eluted with 40% MeOH/H₂O. These are simpleprocedures involving unit operations of mixing, de-gassing, heating,filtration, and solid-phase extraction.

Example 1 (DOPA)Calcium(Carnosine)

FIG. 14 depicts an embodiment including (DOPA)calcium(carnosine). To a2-neck 100 mL round bottom flask equipped with a magnetic stirrer and N₂inlet were added L-DOPA (250.0 mg, 1.27 mmol) and carnosine (286.5 mg,1.27 mmol). Water (50 mL) was added and the mixture heated until thesolids dissolved. Calcium methoxide (129.5 mg, 1.27 mmol) was added inone portion. The orange solution was stirred for 1 hour at roomtemperature. Solvent was removed under reduced pressure leaving a darkbrown solid. ¹H NMR (D₂O) δ 7.66 (s; 1H), 6.93 (s; 1H), 6.74 (d; J=7.8Hz; 1H), 6.66 (d; J=2.2 Hz; 1H), 6.54 (dd; J=7.8 Hz, 2.2 Hz; 1H), 4.47(dd; J=9.2 Hz, 4.6 Hz; 1H), 3.70 (dd; J=7.8 Hz, 5.2 Hz; 1H), 3.13 (dd;J=15.2 Hz, 4.6 Hz; 1H), 3.04-2.99 (m; 3H) 2.95 (dd; J=15.2 Hz, 9.2 Hz;1H), 2.81 (dd; J=14.0 Hz, 7.8 Hz; 1H), 2.57-2.48 (m; 2H).

Carnosine ¹HMR (D₂O) δ 7.71 (s; 1H), 6.95 (s; 1H), 4.47 (dd; J=8.8 Hz,4.8 Hz; 1H), 3.22 (t; J=6.8 Hz; 2H), 3.13 (dd; J=15.2 Hz, 4.8 Hz; 1H),2.97 (dd; J=15.2 Hz, 8.8 Hz; 1H), 2.68-2.63 (m; 2H).

Example 2 (DOPA)Magnesium(Carnosine)—Method 1

FIG. 15 depicts an embodiment of the present disclosure including(DOPA)magnesium(carnosine). To a 2-neck 100 mL round bottom flaskequipped with a magnetic stirrer and N₂ inlet were added L-DOPA (218 mg,1.11 mmol) and carnosine (250 mg, 1.11 mmol). Water (50 mL) was addedand the mixture heated until the solids dissolved. Magnesium t-butoxide(202 mg, 1.11 mmol) was added in one portion. The orange solution wasstirred for 1 hour at room temperature. Solvent was removed underreduced pressure leaving a dark brown solid. ¹H NMR (D₂O) δ 7.67 (s;1H), 6.93 (s; 1H), 6.58 (br d; J=6.4 Hz; 1H), 6.51 (br s; 1H), 6.42 (brd; J=6.4 Hz; 1H), 4.46 (dd; J=9.0 Hz, 4.6 Hz; 1H), 3.78 (dd; J=8.4 Hz,4.8 Hz; 1H), 3.15-3.03 (m; 4H), 2.95 (dd; J=15.2 Hz, 9.0 Hz; 1H), 2.81(dd; J=14.4 Hz, 8.4 Hz; 1H), 2.58-2.54 (m; 2H).

Example 3 (DOPA)Magnesium(Carnosine)—Method 2

FIG. 15 depicts an embodiment of the present disclosure including(DOPA)magnesium(carnosine). To a 50 mL round bottom flask equipped witha magnetic stirrer and N₂ inlet was added carnosine (100 mg, 0.442mmol). DMF (20 mL) was added to form a suspension. Magnesium t-butoxide(80.4 mg, 0.442 mmol) was added in one portion. The suspension wasstirred for 24 hours at room temperature. To the reaction L-DOPA (87.1mg, 0.442 mmol) was added in one portion. The suspension was stirred 24hours. Solvent was removed under reduced pressure leaving a pale yellowsolid. Purification was by SPE. ¹H NMR (D₂O) δ 7.66 (s; 1H), 6.93 (s;1H), 6.54 (br d; J=6.8 Hz; 1H), 6.47 (br s; 1H), 6.39 (br d; J=6.8 Hz;1H), 4.46 (dd; J=8.8 Hz, 4.6 Hz; 1H), 3.75 (dd; J=8.4 Hz, 4.8 Hz; 1H),3.13 (dd; J=15.2 Hz, 4.6 Hz; 1H), 3.06-3.01 (m; 3H), 2.95 (dd; J=15.2Hz, 8.8 Hz; 1H), 2.79 (dd; J=14.4 Hz, 8.4 Hz), 2.56-2.52 (m; 2H). Metalsanalysis: 5.9% Mg (theoretical 5.4%).

Example 4 (SAHA)Magnesium(Mercaptopurine)

FIG. 16 depicts an embodiment of the present disclosure including(SAHA)magnesium(mercaptopurine). To a 25 mL round bottom flask equippedwith magnetic stirrer, heating mantle, and reflux condenser were addedmercaptopurine (57.8 mg, 0.378 mmol) and SAHA (100 mg, 0.378 mmol).Anhydrous methanol (10 mL) was added via syringe and the solids mostlydissolved. Magnesium acetate (81.1 mg, 0.378 mmole) was added and thesuspension was refluxed for 16 hrs; all solids dissolved with heat. Asmall amount of precipitate formed after cooling. The reaction wasvacuum filtered and solvent removed under reduced pressure yielding offwhite solid (170 mg, 0.387 mmole, 102%). ¹H NMR (DMSO-d₆) δ 9.87 (s;1H), 8.30 (s; 1H), 8.20 (s; 1H), 7.58 (d; J=7.6 Hz; 2H), 7.61-7.23 (m;2H), 7.00 (t; J=7.4 Hz; 1H), 2.28 (t; J=7.2 Hz; 2H), 2.03-1.93 (m; 2H),1.62-1.52 (m; 2H), 1.52-1.43 (m; 2H), 1.27 (br s; 3H). ¹³C NMR (DMSO-d₆)δ 171.7 (S8), 171.6 (M6), 169.5 (v. br. S1), 151.2 (M4), 145.4 (M2/M8),145.3 (M8/M2), 139.7 (S10), 129.3 (M5), 129.0 (S11), 123.3 (S12), 119.5(S13), 36.8 (S7), 31.9 (v. br. S2), 28.8 (S6), 28.6 (S3), 25.5 (S4/S5),25.4 (S5/S4). Note: The ¹³C NMR (DMSO-d₆) chemical shift for thecarbonyl carbons of SAHA are 171.7 and 169.5 ppm. The ¹H NMR chemicalshifts for uncoordinated mercaptopurine protons are 8.39 ppm and 8.19ppm.

Example 5 (SAHA)Magnesium(Remacemide)

FIG. 17 depicts an embodiment of the present disclosure including(SAHA)magnesium(remacemide). To a 25 mL round bottom flask equipped withmagnetic stirrer, heating mantle, and reflux condenser were added SAHA(50 mg, 0.189 mmol) and remacemide (50.8 mg, 0.189 mmol). Anhydrousmethanol (10 mL) was added via syringe and the solids dissolved.Magnesium acetate (40.6 mg, 0.189 mmole) was added and immediatelydissolved. The solution was refluxed for 16 hrs. Solvent was removedfrom the clear solution under reduced pressure yielding a colorlesssolid. ¹H NMR (CD₃OD) δ 7.54 (br dd; J=9.2 Hz, 0.8 (av) Hz; 1H),7.34-7.24 (m; 3H), 7.23-7.16 (m; 2H); 7.06 (br t; J=7.4 Hz; 1H),6.97-6.92 (m; 1H), 3.55-3.44 (m; 1H); 3.22-3.17 (m; 1H), 2.35 (t; J=7.6Hz; 1H), 2.10 (t; J=7.6 Hz; 1H), 1.90 (s; 3H); 1.75-1.57 (m; 2H), 1.55(s; 1H), 1.45-1.30 (m; 2H). ¹³C NMR (CD₃OD-d₆) δ 178.7, 173.1, 145.6,138.5, 136.6, 130.5, 128.3, 127.7, 127.4, 126.2, 126.1, 125.2, 123.7,119.8, 58.8, 45.0, 42.0, 36.4, 31.5, 28.5, 28.4, 25.4, 25.3, 22.7. Note:The ¹³C NMR (CD₃OD) chemical shifts for the carbonyl carbons of SAHA are173.2 and 171.5 ppm.

Although the present invention has been described in terms of specificembodiments, changes and modifications can be made without departingfrom the scope of the invention which is intended to be defined only bythe scope of the claims. All references cited herein are herebyincorporated by reference in their entirety, including any referencescited therein.

What is claimed:
 1. A coordination complex, comprising: a firstbiologically active moiety selected from gamma-3-fatty acids,cannabinoids, flupirtine, gluatathione, curcumin, N-acetylcysteine,p-glycoprotein inhibitors, (−)-epigallocatechin-3-gallate, anserine, andhomocarnosine; a second biologically active moiety; and a non-platinummetal; wherein the first and second biologically active moieties areeach bound to the metal by at least one binding site; wherein the firstbiologically active moiety and second biologically active moiety aredifferent; wherein the first biologically active moiety and the secondbiologically active moiety both have a pharmacological effect on atarget tissue.
 2. The coordination complex of claim 1, furthercomprising a ligand.
 3. The coordination complex of claim 2, wherein theligand is selected from salicylaldehyde, dipyridyl, and ethylenediamine.4. The coordination complex of claim 1, wherein the metal is selectedfrom the group consisting of magnesium, calcium, iron, cobalt, nickel,copper, zinc, palladium, ruthenium, rhodium, aluminum, cadmium,vanadium, chromium, strontium, and tin.
 5. The coordination complex ofclaim 1, further comprising a component selected from the groupconsisting of an amino acid, a lipid, a carbohydrate, a nucleic acid,and a peptide.
 6. A method for enhancing the treatment of a disease,comprising: forming a coordination complex comprising a firstbiologically active moiety selected from selected from gamma-3-fattyacids, cannabinoids, flupirtine, glutathione, curcumin,N-acetylcysteine, p-glycoprotein inhibitors,(−)-epigallocatechin-3-gallate, anserine, and homocarnosine; a secondbiologically active moiety, and a non-platinum metal; wherein the firstbiologically active moiety and the second biologically active moiety areeach bound to the metal by at least one binding site; wherein the firstbiologically active moiety and the second biologically active moiety aredifferent.
 7. The method of claim 6, wherein the coordination complexformed includes a ligand.
 8. The method of claim 7, wherein the ligandis selected from salicylaldehyde, dipyridyl, and ethylenediamine.
 9. Themethod of claim 6, wherein the metal is selected from the groupconsisting of magnesium, calcium, iron, cobalt, nickel, copper, zinc,palladium, ruthenium, rhodium, aluminum, cadmium, vanadium, chromium,strontium, and tin.
 10. The method of claim 6, further comprising acomponent selected from the group consisting of an amino acid, a lipid,a carbohydrate, a nucleic acid, and a peptide.
 11. A method of treatinga disease, comprising: administering a coordination complex comprising afirst biologically active moiety selected from selected fromgamma-3-fatty acids, cannabinoids, flupirtine, glutathione, curcumin,N-acetylcysteine, p-glycoprotein inhibitors,(−)-epigallocatechin-3-gallate, anserine, and homocarnosine; a secondbiologically active moiety, and a non-platinum metal to a patient havinga disease; wherein the first and second biologically active moietiestreat a disease by interacting with one or more tissues associated withthe disease.
 12. The method of claim 11, wherein the coordinationcomplex formed includes a ligand.
 13. The method of claim 12, whereinthe ligand is selected from salicylaldehyde, dipyridyl, andethylenediamine.
 14. The method of claim 11, wherein the metal isselected from the group consisting of magnesium, calcium, iron, cobalt,nickel, copper, zinc, palladium, ruthenium, rhodium, aluminum, cadmium,vanadium, chromium, strontium, and tin.
 15. The method of claim 11,further comprising a component selected from the group consisting of anamino acid, a lipid, a carbohydrate, a nucleic acid, and a peptide.